Polymorphic forms of Dasatinib

ABSTRACT

The present invention provides for the dasatinib-thymine co-crystal and dasatinib-adenine co-crystal. The present invention further provides dasatinib-butanediol solvate. The present invention further provides for crystalline dasatinib-(±)-1, 2-Butanediol, crystalline dasatinib (R)-1, 2-Butanediol, crystalline dasatinib (S)-1, 2-Butanediol and crystalline dasatinib (±)-2, 3-Butanediol and processes for preparation thereof. The present invention also provides for a process for preparation of amorphous dasatinib using dasatinib-butanediol solvate. The present invention further provides for the preparation of anhydrous dasatinib. The present invention also provides for a process for preparation of dasatinib monohydrate from anhydrous dasatinib.

RELATED APPLICATION

This application is a U.S. National Stage entry of InternationalApplication No. PCT/IB2018/055022 filed Jul. 7, 2018, which claims thebenefit of IN Patent Application 201841007613, filed Feb. 28, 2018, INPatent Application 201841001249, filed Jan. 11, 2018, IN PatentApplication 201741029965, filed Aug. 24, 2017, and IN Patent ApplicationNo. 201741024067, filed Jul. 7, 2017, each of which is hereinincorporated by reference in its entirety for all purposes.

TECHNICAL FIELD

The present invention relates to polymorphic forms of dasatinib. Inparticular, the invention relates to co-crystals and solvates ofdasatinib and processes for the preparation thereof.

BACKGROUND AND PRIOR ART OF THE DISCLOSURE

SPRYCEL® (Dasatinib monohydrate) is a kinase inhibitor. The chemicalname for Dasatinib monohydrate isN-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-thiazolecarboxamide, monohydrate which is having molecularFormula C₂₂H₂₆ClN₇O₂S. H₂O and molecular weight 506.02 (monohydrate) andits structural Formula is as follows,

SPRYCEL® is a kinase inhibitor indicated for the treatment of newlydiagnosed adults with Philadelphia chromosome-positive (Ph+) chronicmyeloid leukemia (CML) in chronic phase, adults with chronic,accelerated or myeloid or lymphoid blast phase Ph+ CML with resistanceor intolerance to prior therapy including imatinib and adults withPhiladelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)with resistance or intolerance to prior therapy.

Dasatinib which was disclosed in PCT Publication No. WO 00/62778 and inU.S. Pat. No. 6,596,746. Dasatinib, chemicallyN-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide.

Dasatinib is known to exist in various solid-state forms: a monohydrate,four anhydrous and unsolvated forms that are described in U.S. Pat. No.7,491,725 B2, US2006/0004067A1, U.S. Pat. No. 7,973,045 B2 andWO2010/067374 and therein referred to as forms N-6, T1H1-7, B and I.

U.S. Pat. No. 8,067,423 B2 discloses an amorphous form and solvates ofIPA, THF, 2-MeTHF, 1,4-Dioxane, Pyridine, Toluene, MIBK, Mono acetone,2-Butanol-DMSO, IPA-DMF, n-Propanol-DMF, n-Propanol, 2-Butanol-DMF,2-Butanol, n-Butanol-DMSO, DMF-water, DMF, MIPK, Dimethoxy ethane,Cellosolve, Methyl acetate, Methanol, Ethyl acetate, 2-Pentanone,Dimethyl carbonate, Isopropyl acetate, Dichloromethane, Methyl formate,t-Butanol, MEK, Monochloro benzene, PGME, Cyclopentyl methyl ether,MTBE, Amyl alcohol, Dimethyl carbonate, Ethylene glycol and glycerol.

PCT publication WO2007/035874 A1 discloses crystalline form of amono-hydrochloric acid salt of Dasatinib comprising Form CA-2, secondcrystalline form of a mono-hydrochloric acid salt of Dasatinibcomprising Form HAC2-1, crystalline form of a di-hydrochloric acid saltof Dasatinib comprising Form H3-1, crystalline form of a monosulfuricacid salt of Dasatinib comprising Form SB-2, second crystalline form ofa monosulfuric acid salt of Dasatinib comprising Form SD-2, crystallineform of a hemisulfuric acid salt of Dasatinib comprising Form SA-I,second crystalline form of a hemisulfuric acid salt of Dasatinibcomprising Form SC-I, crystalline form of an acetic acid salt ofDasatinib comprising Form NMP-I, a crystalline form of a phosphoric acidsalt of Dasatinib comprising Form SA-I, a crystalline form of ahydrobromic acid salt of Dasatinib comprising Form H1.5-1, a crystallineform of a fumaric acid salt of Dasatinib comprising Form TO-I, acrystalline form of a salicylic acid salt of Dasatinib comprising FormSS-2, a crystalline form of a tartaric acid salt of Dasatinib, acrystalline form of a methanesulfonic acid salt of Dasatinib comprisingForm PG-I, a crystalline form of a maleic acid salt of Dasatinibcomprising Form E-1, a crystalline form of a maleic acid salt ofDasatinib comprising Form H3-2 and a crystalline form of ap-toluenesulfonic acid salt of Dasatinib comprising Form N-1.

Chinese patent CN102030745 discloses a crystalline solvate YE ofDasatinib and isopropyl ether.

Furthermore, Dasatinib solvates are known from US2006/0004067A,WO2010/062715, and in particular, patent application WO 2010/062715includes the solvates of isosorbide dimethyl ether,N,N′-dimethylethylene urea and N,N′-dimethyl-N,N′-propylene urea.Isosorbide dimethyl ether is used in cosmetic and pharmaceuticalFormulations.

PCT publication WO2013/186726 A2 discloses various co-crystals withDasatinib such as Dasatinib-Methyl-4-hydroxy-benzoate co-crystal (3:1),Dasatinib-Nicotinamide co-crystal (3:1), Dasatinib-Ethyl gallateco-crystal (3:1), Dasatinib-Vanillin co-crystal (3:1), Dasatinib-Methylgallate co-crystal (3:1) and Dasatinib-(1R,2S,5R)-(−)-Menthol co-crystal(3:1).

This invention as disclosed in WO2013/186726 A2 suffers from followingdisadvantages.

-   -   Dasatinib and co-former molar ratio in co-crystal is the same as        the molar ratio of input.    -   The volume of the solvent used is huge (>75 vol) which may not        be suitable for the scale up.    -   The isolation procedure involves the complete evaporation of the        reaction mass under dry nitrogen flow, which may not be suitable        for scale up.    -   The input for the formation of Dasatinib co-crystals is        Dasatinib monohydrate. PCT publication WO2016/001025 A1        discloses various co-crystals such as        Dasatinib-(1R,2S,5R)-(−)-Menthol co-crystal (2:1) and        Dasatinib-Vanillin co-crystal (1:1).

This invention as disclosed in WO2016/001025 A1 suffers from followingdisadvantages.

-   -   The process for the preparation of        Dasatinib-(1R,2S,5R)-(−)-Menthol co-crystal (2:1) involves        heating to 120° C. under neat condition which may not be        suitable for scale up.    -   The process for the preparation of        Dasatinib-(1R,2S,5R)-(−)-Menthol co-crystal (2:1) involves        filtration at 90° C. which may not be suitable for scale up.    -   The process for the preparation of Dasatinib-Vanillin co-crystal        (1:1) involves heating to 120° C. under neat condition, which        may not be suitable for scale up.    -   The input for the formation of Dasatinib co-crystals is        Dasatinib monohydrate.

PCT publication WO2017/002131 A1 discloses Dasatinib-1,2-Propanediolsolvate and process for the preparation of Dasatinib-1,2-Propanediolsolvate.

This invention as disclosed in WO2017/002131 A1 suffers from followingdisadvantages.

-   -   Solvent required to prepare and get Dasatinib-1,2-Propanediol        solvate is huge as around 21 volume of solvent is used.    -   Process involves wet solid isolation followed by 40 volume of        solvent usage to get the pure solvate, which means an impure wet        solid is used.

PCT Publication WO 20171/034615 A1 also disclosesDasatinib-1,2-Propanediol solvate and process for the preparation ofDasatinib-1,2-Propanediol solvate.

-   -   Dasatinib-1,2-Propanediol solvate formation requires 12 volumes        of solvent, which again is not economical.    -   BHT is used in the solvate formation to prevent the formation of        N-oxide related impurities.

SUMMARY OF THE INVENTION

Aspects of the present application provides co-crystals and solvates ofdasatinib and safe, simpler & economical processes for the preparationthereof. Each step of the process disclosed herein are contemplated bothin the context of the multistep sequences described and individually.

First aspect of the present invention is crystalline Dasatinib-Thymineco-crystal of Formula Ia.

Second aspect of the present invention, the crystallineDasatinib-Thymine co-crystal of Formula Ia is characterized by ¹H NMRwhich is in accordance with the FIG. 1.

Third aspect of the present invention, the crystalline Dasatinib-Thymineco-crystal of Formula Ia is further characterised by DSC havingendotherm at around 260° C. and the DSC pattern in accordance with theFIG. 2.

Fourth aspect of the present invention, the crystallineDasatinib-Thymine co-crystal of Formula Ia is further characterised byPXRD having the main 2-theta values 6.83±0.2, 7.15±0.2, 12.15±0.2,13.27±0.2, 13.64±0.2, 14.29±0.2, 16.31±0.2, 16.67±0.2, 17.30±0.2,18.32±0.2, 18.78±0.2, 19.18±0.2, 20.56±0.2, 21.42±0.2, 21.90±0.2,22.40±0.2, 23.94±0.2, 24.39±0.2, 26.76±0.2, 27.37±0.2, 27.70±0.2,28.77±0.2, 29.28±0.2, 30.21±0.2, 31.39±0.2, 34.32±0.2, 36.14±0.2,43.75±0.2 and the PXRD pattern in accordance with the FIG. 3.

TABLE 1 Num. Gonio d Int I/Imax  1  6.8396 12.9133 495 22.1  2  7.156712.342 2245 100.0  3 12.1553 7.27546 124 5.5  4 13.2770 6.66323 250 11.2 5 13.6481 6.48289 203 9.0  6 14.2953 6.19078 516 23.0  7 16.31065.43014 90 4.0  8 16.6718 5.3133 158 7.1  9 17.3082 5.11933 37 1.6 1018.3283 4.83664 58 2.6 11 18.7851 4.72004 42 1.9 12 19.1824 4.62317 703.1 13 20.5697 4.3144 61 2.7 14 21.4246 4.14412 66 3.0 15 21.90154.05495 108 4.8 16 22.4019 3.96549 41 1.8 17 23.9490 3.71272 91 4.0 1824.3900 3.64658 78 3.5 19 26.7672 3.32787 38 1.7 20 27.3775 3.25506 1125.0 21 27.7041 3.21742 67 3.0 22 28.7768 3.09988 40 1.8 23 29.28593.04713 36 1.6 24 30.2100 2.956 64 2.9 25 31.3934 2.84722 36 1.6 2634.3268 2.61032 32 1.4 27 36.1430 2.48321 26 1.2 28 43.7583 2.06708 281.2

Fifth aspect of the present invention provides the process for thepreparation of crystalline Dasatinib-Thymine co-crystal of Formula Ia.

wherein the process does not involve the isolation of Dasatinib asintermediate.

Sixth aspect of the present invention provides the process for thepreparation of crystalline Dasatinib-Thymine co-crystal of Formula Ia.

comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in a suitable organic solvent at a suitable temperature to obtainFormula I in situ

treating with Thymine in a suitable solvent/s at a suitable temperature,

to obtain crystalline Dasatinib-Thymine co-crystal of Formula Ia.

Further, the present invention relates to the process for thepreparation for crystalline Dasatinib-Thymine co-crystal of Formula Iacomprising following steps,

-   -   a) Charging Dichloro intermediate of Formula II into a reactor    -   b) Adding 2-(piperazin-1-yl) ethan-1-ol of Formula III    -   c) Adding a suitable organic solvent    -   d) Heating the reaction mass to a suitable temperature    -   e) Maintaining the reaction mass at a suitable temperature    -   f) Cooling the reaction mass to a suitable temperature    -   g) Adding Thymine at a suitable temperature    -   h) Adding a suitable organic solvent to the reaction mass at a        suitable temperature    -   i) Heating the reaction mixture to a suitable temperature    -   j) Maintaining the reaction mixture at a suitable temperature    -   k) Cooling the reaction mixture to a suitable temperature    -   l) Stirring the reaction mixture at a suitable temperature    -   m) Adding water to the reaction mixture at a suitable        temperature    -   n) Stirring the reaction mixture at a suitable temperature    -   o) Filtering the reaction mixture under vacuum    -   p) Washing the solid with a suitable organic solvent    -   q) Suck drying the wet solid under vacuum    -   r) Drying the wet solid at a suitable temperature under vacuum        to obtain crystalline Dasatinib-Thymine co-crystal of Formula        Ia.

Further, according to step c), as described above, a suitable organicsolvent is selected from the group consisting of solvents selected fromN,N-Dimethylacetamide, N,N-Dimethylformamide and the like.

Further, according to step d) and step e), suitable temperature isselected from the range consisting of 40 to 80° C., preferably 70 to 8°C.

Further, in step f), step g) and step h), a suitable temperature isselected from the range consisting of 20 to 60° C., preferably 20 to 40°C., more preferably 20 to 30° C.

Further, in step i) and step j), a suitable temperature is selected fromthe range consisting of 30 to 62° C., preferably 50 to 62° C.

Further, in step k), step l), step m) and step n), a suitabletemperature is selected from the range consisting of 10 to 40° C.,preferably 10 to 30° C., more preferably 20 to 30° C.

Further, in step h) and step p), a suitable organic solvent is selectedfrom the group consisting of Alcoholic solvents selected from methanol,ethanol, propanol, n-butanol & isopropanol.

Further, in step r), a suitable temperature is selected from the rangeconsisting of 30 to 65° C., preferably 45 to 65° C., more preferably 50to 60° C.

Seventh aspect of the present invention provides the process for thepreparation of crystalline Dasatinib-Thymine co-crystal of Formula Ia.

comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in a suitable organic solvent at a suitable temperature and isolatingFormula I as a wet solid using a suitable organic solvent at a suitabletemperature.

Treating the wet solid of Formula I with Thymine

In a suitable solvent/s at a suitable temperature, to obtain crystallineDasatinib-Thymine co-crystal of Formula Ia,

Eighth aspect of the present invention relates to the alternate processfor the preparation of a crystalline Dasatinib-Thymine co-crystal ofFormula Ia, comprising the following steps,

Treating the Dichloro intermediate of Formula I

S with 2-(piperazin-1-yl)ethan-1-ol of Formula III

and Thymine,

in a suitable solvent at a suitable temperature, to obtain a crystallineDasatinib-Thymine co-crystal of Formula n,

Further, the present invention relates to the alternate process for thepreparation of crystalline Dasatinib-Thymine co-crystal of Formula I,comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding Thymine at a suitable temperature    -   d) adding a suitable organic solvent    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding a suitable organic solvent at a suitable temperature    -   h) maintaining the reaction mass at a suitable temperature    -   i) cooling the reaction mass to a suitable temperature    -   j) stirring the reaction mixture at a suitable temperature    -   k) filtering the reaction mixture under vacuum    -   l) washing the solid with a suitable organic solvent    -   m) suck drying the wet solid under vacuum    -   n) drying the wet solid at a suitable temperature under vacuum        to obtain a crystalline Dasatinib-Thymine co-crystal of Formula        Ia

Further, in step d), step g) and step l), a suitable organic solvent isselected from the group consisting of alcoholic solvents, preferablyMethanol.

Further, in step e), step f), step g) and step h), a suitabletemperature is selected from the range consisting of 30 to 69° C.,preferably 50 to 69° C., more preferably 65 to 69° C.

Further, in step i) and step j), a suitable temperature is selected fromthe range consisting of 10 to 40° C., preferably 10 to 30° C., morepreferably 20 to 30° C.

Further, in step n), a suitable temperature is selected from the rangeconsisting of 30 to 65° C., preferably 45 to 65° C., more preferably 50to 60° C.

Ninth aspect of the present invention is crystalline Dasatinib-Adenineco-crystal of Formula Ib.

Tenth aspect of the present invention, the crystalline Dasatinib-Adenineco-crystal of Formula Ib is characterized by ¹H NMR which is inaccordance with the FIG. 4.

Eleventh aspect of the present invention, the crystallineDasatinib-Adenine co-crystal of Formula Ib is further characterized byDSC having endotherm at around 274.4° C. and the DSC pattern inaccordance with the FIG. 5.

Twelfth aspect of the present invention, the crystallineDasatinib-Adenine co-crystal of Formula Ib is further characterized byPXRD having the main 2-theta values 6.91±0.2, 7.25±0.2, 12.37±0.2,13.25±0.2, 13.78±0.2, 14.47±0.2, 15.99±0.2, 16.57±0.2, 16.74±0.2,17.21±0.2, 18.53±0.2, 19.25±0.2, 20.99±0.2, 21.89±0.2, 22.07±0.2,22.51±0.2, 23.12±0.2, 23.82±0.2, 24.31±0.2, 24.82±0.2, 25.29±0.2,27.99±0.2, 32.22±0.2, 38.72±0.2. and the PXRD pattern in accordance withthe FIG. 6.

TABLE 2 Num Gonio d Int T/Imax  1  6.9166 12.7698 1256 100.0  2  7.253612.1773 241 19.2  3 12.3736 7.14762 141 11.3  4 13.2538 6.67486 411 32.7 5 13.7862 6.41824 521 41.5  6 14.4786 6.11283 165 13.1  7 15.99375.53701 338 26.9  8 16.5710 5.34538 114 9.1  9 16.7485 5.28913 135 10.710 17.2129 5.14746 66 5.2 11 18.5321 4.7839 77 6.1 12 19.2549 4.60592 685.4 13 20.9917 4.22859 48 3.8 14 21.8952 4.05611 89 7.1 15 22.07654.02321 104 8.3 16 22.5182 3.94528 46 3.7 17 23.1230 3.84344 52 4.1 1823.8207 3.73241 63 5.0 19 24.3132 3.65791 81 6.4 20 24.8265 3.58343 705.6 21 25.2906 3.51872 50 4.0 22 27.9983 3.18427 166 13.2 23 32.22802.77536 34 2.7 24 38.7229 2.3235 29 2.3

Thirteenth aspect of the present invention provides the process for thepreparation of crystalline Dasatinib-Adenine co-crystal of Formula Ib.

wherein the process does not involve the isolation of Dasatinib.

Fourteenth aspect of the present invention provides the process for thepreparation of crystalline Dasatinib-Adenine co-crystal of Formula Ib.

Comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in a suitable organic solvent at a suitable temperature to obtainFormula I in situ

Treating the with Adenine

In a suitable solvent/s at a suitable temperature, to obtain crystallineDasatinib-Adenine co-crystal of Formula Ib,

Further, the present invention relates to the process for thepreparation for crystalline Dasatinib-Adenine co-crystal of Formula Ibcomprising following steps,

a) Charging Dichloro intermediate of Formula II into a reactor

b) Adding 2-(piperazin-1-yl) ethan-1-ol of Formula III

c) Adding a suitable organic solvent

d) Heating the reaction mass to a suitable temperature

e) Maintaining the reaction mass at a suitable temperature

f) Cooling the reaction mass to a suitable temperature

g) Adding Adenine at a suitable temperature

h) Adding a suitable organic solvent to the reaction mass at a suitabletemperature

i) Heating the reaction mixture to a suitable temperature

j) Maintaining the reaction mixture at a suitable temperature

k) Cooling the reaction mixture to a suitable temperature

l) Stirring the reaction mixture at a suitable temperature

m) Adding water to the reaction mixture at a suitable temperature

n) Stirring the reaction mixture at a suitable temperature

o) Filtering the reaction mixture under vacuum

p) Washing the solid with a suitable organic solvent

q) Suck drying the wet solid under vacuum

r) Drying the wet solid at a suitable temperature under vacuum to obtaincrystalline Dasatinib-Adenine co-crystal of Formula Ib.

Further, according to step c), as described above, a suitable organicsolvent is selected from the group consisting of solvents selected fromN,N-Dimethylacetamide, N,N-Dimethylformamide and the like.

Further, according to step d) and step e), suitable temperature isselected from the range consisting of 40 to 80° C., preferably 70 to 80°C.

Further, in step f), step g) and step h), a suitable temperature isselected from the range consisting of 20 to 60° C., preferably 20 to 40°C., more preferably 20 to 30° C.

Further, in step i) and step j), a suitable temperature is selected fromthe range consisting of 30 to 62° C., preferably 50 to 62° C.

Further, in step k), step l), step m) and step n), a suitabletemperature is selected from the range consisting of 10 to 40° C.,preferably, 10 to 30° C., more preferably 20 to 30° C.

Further, in step h) and step p), a suitable organic solvent is selectedfrom the group consisting of Alcoholic solvents selected from methanol,ethanol, propanol, n-butanol & isopropanol.

Further, in step r), a suitable temperature is selected from the rangeconsisting of 30 to 65° C., preferably 45 to 65° C., more preferably 50to 60° C.

Fifteenth aspect of the present invention relates to the alternateprocess for the preparation of a crystalline Dasatinib-Adenineco-crystal Formula Ib, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in a suitable organic solvent at a suitable temperature to obtainFormula I (wet)

treating the wet Formula I with Adenine

in a suitable solvent/s at suitable temperature, to obtain crystallineDasatinib-Adenine co-crystal of Formula Ib,

Further, the present invention relates to the alternate process for thepreparation of a crystalline Dasatinib-Adenine co-crystal comprising thefollowing steps,

-   -   a) charging Dichloro intermediate of Formula I into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) heating the reaction mass to a suitable temperature    -   e) maintaining the reaction mass at a suitable temperature    -   f) cooling the reaction mass to a suitable temperature    -   g) adding a suitable organic solvent at a suitable temperature    -   h) stirring the reaction mixture at a suitable temperature    -   i) filtering the reaction mixture under vacuum    -   j) washing the solid with a suitable organic solvent    -   k) suck drying the wet solid under vacuum    -   l) transferring the wet solid into a reactor    -   m) adding Adenine    -   n) adding a suitable organic solvent    -   o) heating the reaction mixture to a suitable temperature    -   p) maintaining the reaction mixture at a suitable temperature    -   q) cooling the reaction mixture to a suitable temperature    -   r) stirring the reaction mixture at a suitable temperature    -   s) adding water to the reaction mixture at a suitable        temperature    -   t) stirring the reaction mixture at a suitable temperature    -   u) filtering the reaction mixture under vacuum    -   v) washing the solid with a suitable organic solvent    -   w) suck drying the wet solid under vacuum    -   x) drying the wet solid at a suitable temperature under vacuum        to obtain crystalline Dasatinib-Adenine co-crystal of Formula Ib

Further, in step c), a suitable organic solvent selected from the groupconsisting of Amide solvents, preferably N,N-Dimethylacetamide.

Further, in step d) and step e), a suitable temperature selected fromthe range consisting of 40 to 80° C., preferably 70 to 80° C., morepreferably 73 to 77° C.

Further, in step f), step g), step h), step q), step r), step s) andstep t) a suitable temperature selected from the range consisting of 20to 60° C., preferably 20 to 40° C., more preferably 20 to 30° C.

Further, in step o) and step p), a suitable temperature selected fromthe range consisting of 30 to 62° C., preferably 50 to 62° C., morepreferably 58 to 62° C.

Further, in step g), step j), step n) and step v), a suitable organicsolvent selected from the group consisting of Alcoholic solvents,preferably Methanol.

Further, in step x), a suitable temperature selected from the rangeconsisting of 30 to 65° C., preferably 45 to 65° C., more preferably 50to 60° C.

Sixteenth aspect of the present invention relates to the alternateprocess for the preparation of a crystalline Dasatinib-Adenineco-crystal Formula Ib, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

and Adenine,

in a suitable solvent at suitable temperature, to obtain crystallineDasatinib-Adenine co-crystal of Formula Ib,

Further, the present invention relates to the alternate process for thepreparation of crystalline Dasatinib-Adenine co-crystal of Formula Ib,further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding Adenine    -   d) adding a suitable organic solvent    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding a suitable organic solvent at a suitable temperature    -   h) maintaining the reaction mass at a suitable temperature    -   i) cooling the reaction mass to a suitable temperature    -   j) stirring the reaction mixture at a suitable temperature    -   k) filtering the reaction mixture under vacuum    -   l) washing the solid with a suitable organic solvent    -   m) suck drying the wet solid under vacuum    -   n) drying the wet solid at a suitable temperature under vacuum        to obtain crystalline Dasatinib-Adenine co-crystal of Formula Ib

Further, in step d), step g) and step l), a suitable organic solvent isselected from the group consisting of alcoholic solvents, preferablyMethanol.

Further, in step e), step f), step g) and step h), a suitabletemperature is selected from the range consisting of 30 to 62° C.,preferably 50 to 62° C., more preferably 58 to 62° C.

Further, in step i) and step j), a suitable temperature is selected fromthe range consisting of 10 to 40° C., preferably 10 to 30° C., morepreferably 20 to 30° C.

Further, in step n), a suitable temperature is selected from the rangeconsisting of 30 to 65° C., preferably 45 to 65° C., more preferably 50to 60° C.

Seventeenth aspect of the present invention providesDasatinib-alkanediol solvates.

Eighteenth aspect of the present invention provides crystallineDasatinib-alkanediol solvate.

Nineteenth aspect of the present invention provides alkanediol solventchosen from linear alkyl chain having carbon length C4-C7.

Twentieth aspect of the present invention provides alkanediol solventselected preferably from alkyl chain having carbon length C4-C7 whereinthe diols are vicinal.

Twenty first aspect of the present invention provides alkanediol solventselected preferably from alkyl chain having carbon length C4-C7 wherein,the diols can be racemic and/or absolute stereoisomers.

Twenty second aspect of the present invention provides alkanediolsolvent was selected preferably from alkyl chain having carbon lengthC4-C7 and most preferably, alkyl chain having carbon length C4 wherein,the diols can be racemic and/or absolute stereoisomers.

Twenty third aspect of the present invention providesDasatinib-butanediol solvate.

Twenty fourth aspect of the present invention provides crystallineDasatinib-butanediol solvate.

Twenty fifth aspect of the present invention provides a process for thepreparation of a crystalline Dasatinib-Butanediol solvate of Formula Icor Formula Id or Formula Ie or Formula g, comprising the followingsteps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable Butanediol and a suitable organic base atsuitable temperature, to obtain corresponding a crystallineDasatinib-Butanediol solvate of Formula Ic or Formula Id or Formula Ieor Formula Ig

Wherein, Butanediol=(±)-1,2-Butane diol or (R)-1,2-Butanediol or(S)-1,2-Butanediol or (±)-2,3-Butanediol

Formula Ic=Dasatinib-(±)-1,2-Butanediol

Formula Id=Dasatinib-(R)-1,2-Butanediol solvate

Formula Ie=Dasatinib-(S)-1,2-Butanediol solvate

Formula Ig=Dasatinib-(±)-2,3-Butanediol solvate

Further, the present invention relates to the process for thepreparation for crystalline Dasatinib-butane diol solvate of Formula Ior Formula Id or Formula Ie or Formula Ig comprising following steps,

-   -   a) Charging Dichloro intermediate of Formula II into a reactor    -   b) Adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) Optionally a suitable organic solvent and adding a suitable        butanediol    -   d) Optionally adding a suitable organic base    -   e) Heating the reaction mass to a suitable temperature    -   f) Maintaining the reaction mass at a suitable temperature    -   g) Cooling the reaction mass to a suitable temperature    -   h) Stirring the reaction mixture at a suitable temperature    -   i) Filtering the reaction mixture under vacuum    -   j) Suck drying the wet solid under vacuum    -   k) Optionally washing with wet solid with a suitable organic        solvent    -   l) Optionally drying the wet solid at a suitable temperature        under vacuum to obtain corresponding crystalline        Dasatinib-butanediol solvate of Formula Ic or Formula Id or        Formula Ie or Formula Ig.

Further according to step c), a suitable organic solvent selected fromthe group consisting of Amide solvents, preferablyN,N-Dimethylacetamide.

Further according to step c), the suitable butanediol is selected fromthe group of vicinal Butanediol, preferably isomer and isomeric mixtureof 1,2-butane diols or 2,3-butanediol, more preferably(±)-1,2-butanediol or (R)-1,2-butanediol or (S)-1,2-butanediol or(±)-2,3-butanediol

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 90 to 120° C., preferably 100 to120° C., more preferably 110 to 120° C.

Further according to step g) and step h), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step k), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step l), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably 30 to 45° C., morepreferably 35 to 45° C.

Twenty sixth aspect of the present invention provides an alternateprocess for the preparation of crystalline Dasatinib-Butanediol solvateof Formula Ic or Formula Id or Formula Ie or Formula Ig comprising thefollowing steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of suitable organic solvent and a suitable organic baseat a suitable temperature to obtain Formula I (In-situ)

treating the mass containing the Formula I with a suitable Butanediol ata suitable temperature, to obtain crystalline Dasatinib-Butanediolsolvate of Formula Ic or Formula Id or Formula Ie or Formula Ig,

Wherein, Butanediol=(±)-1,2-Butane diol or (R)-1,2-Butanediol or(S)-1,2-Butanediol or (±)-2,3-Butanediol

Formula Ic=Dasatinib-(±)-1,2-Butane diol solvate

Formula Id=Dasatinib-(R)-1,2-Butanediol solvate

Formula Ie=Dasatinib-(S)-1,2-Butanediol solvate

Formula Ig=Dasatinib-(±)-2,3-Butane diol solvate

Further, the present invention relates to the process for thepreparation for crystalline Dasatinib-butane diol solvate of Formula kor Formula Id or Formula Ie or Formula Ig comprising following steps,

-   -   a) Charging Dichloro intermediate of Formula II into a reactor    -   b) Adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) Adding a suitable organic solvent    -   d) Optionally addition suitable organic base    -   e) Heating the reaction mass to a suitable temperature    -   f) Maintaining the reaction mass at a suitable temperature    -   g) Adding a suitable Butanediol at a suitable temperature    -   h) Heating the reaction mass to a suitable temperature    -   i) Maintaining the reaction mass at a suitable temperature    -   j) Cooling the reaction mass to a suitable temperature    -   k) Stirring the reaction mixture at a suitable temperature    -   l) Filtering the reaction mixture under vacuum    -   m) Suck drying the wet solid under vacuum    -   n) Optionally washing with wet solid with as suitable organic        solvent    -   o) Optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-Butanediol solvate        of Formula Ic or Formula Id or Formula Ie or Formula Ig.

Further according step c), a suitable organic solvent is selected from,Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferably N,N-Dimethylacetamide

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferably Diisopropylethylamineor Triethylamine, more preferably Triethylamine.

Further according to step e) step f) and step g), a suitable temperatureis selected from the range consisting of 30 to 90° C., preferably, 60 to90° C., more preferably 83 to 87° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 30 to 122° C., preferably, 90 to122° C., more preferably 118 to 122° C.

Further according to step g), the suitable butanediol is selected fromthe group of vicinal Butanediol, preferably isomer and isomeric mixtureof 1,2-butane diols or 2,3-butanediols, more preferably(=)-1,2-butanediol or (R)-1,2-butanediol or (S)-1,2-butanediol or(±)-2,3-butanediol

Further according to step j) and step k), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step o), a suitable temperature is selected fromthe range consisting of 20 to 45° C. preferably 30 to 45° C., morepreferably 35 to 45° C.

Twenty seventh aspect of the present invention provides the crystallineDasatinib-(±)-1,2-Butanediol solvate.

Twenty eighth aspect of the present invention, the crystallinecrystalline Dasatinib-(±)-1,2-Butanediol solvate of Formula Ic isfurther characterized by PXRD having the main 2-theta values 5.61±0.2,8.05±0.2, 10.99±0.2, 11.22±0.2, 12.50±0.2, 13.53±0.2, 14.59±0.2,14.99±0.2, 16.84±0.2, 17.25±0.2, 17.58±0.2, 18.23±0.2, 19.18±0.2,19.83±0.2, 20.46±0.2, 21.32±0.2, 21.70±0.2, 22.05±0.2, 22.49±0.2,23.44±0.2, 24.11±0.2, 24.78±0.2, 25.51±0.2, 26.16±0.2, 27.12±0.2,27.56±0.2, 30.86±0.2, 32.48±0.2, 32.96±0.2, 35.29±0.2, 37.23±0.2,39.53±0.2, 43.69±0.2 and the PXRD pattern in accordance with the FIG. 9.

TABLE 3 Num. Gonio d Int I/Imax  1  5.6129 15.7326 1968 100.0  2  8.053110.97 37 1.9  3 10.9986 8.03792 331 16.8  4 11.2278 7.87431 825 41.9  512.5005 7.07534 211 10.7  6 13.5312 6.5386 148 7.5  7 14.5921 6.06552 482.4  8 14.9888 5.90589 57 2.9  9 16.8432 5.2596 286 14.5 10 17.25075.13627 247 12.5 11 17.5868 5.03886 81 4.1 12 18.2315 4.8621 136 6.9 1319.1891 4.62157 41 2.1 14 19.8307 4.47348 33 1.7 15 20.4695 4.33528 402.0 16 21.3272 4.16282 52 2.6 17 21.7065 4.09093 232 11.8 18 22.05524.02705 191 9.7 19 22.4974 3.94887 148 7.5 20 23.4493 3.79069 41 2.1 2124.1118 3.68801 356 18.1 22 24.7884 3.58886 80 4.1 23 25.5180 3.48788 442.2 24 26.1639 3.40322 79 4.0 25 27.1239 3.28491 143 7.3 26 27.56273.2336 144 7.3 27 30.8607 2.89514 38 2.0 28 32.4825 2.7542 36 1.8 2932.9697 2.7146 26 1.3 30 35.2984 2.54067 33 1.7 31 37.2388 2.41261 311.6 32 39.5349 2.27762 33 1.7 33 43.6962 2.06988 26 1.3

Twenty ninth aspect of the present invention, the crystallinecrystalline Dasatinib-(±)-1,2-Butanediol solvate of Formula Ic isfurther characterized by DSC having endotherms at around 169.5 & 285.4°C. and the DSC pattern in accordance with the FIG. 8.

Thirtieth aspect of the present invention provides a process for thepreparation of crystalline Dasatinib-(±)-1,2-butanediol solvate ofFormula Ie, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and (=)-1,2-Butanediol anda suitable organic base at a suitable temperature, to obtaincorresponding crystalline Dasatinib-(±)-1,2-butanediol solvate ofFormula Ic,

Further, the present invention relates to the process for thepreparation of a crystalline Dasatinib-(±)-1,2-butanediol solvate ofFormula Ic, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) optionally adding a suitable organic solvent and adding        (±)-1,2-butanediol    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) cooling the reaction mass to a suitable temperature    -   h) stirring the reaction mixture at a suitable temperature    -   i) filtering the reaction mixture under vacuum    -   j) suck drying the wet solid under vacuum    -   k) optionally washing with wet solid with a suitable organic        solvent    -   l) optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(±)-1,2-Butanediol        solvate of Formula Ic

Further according to step c), a suitable organic solvent is selectedfrom, Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferablyN,N-Dimethyl acetamide

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 90 to 120° C., preferably, 100 to120° C., more preferably 110 to 120° C.

Further according step g) and step h), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably, 50 to65° C., more preferably 55 to 65° C.

Further according to step k), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step l), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably, 30 to 45° C., morepreferably 35 to 45° C.

Thirty first aspect of the present invention provides an alternateprocess for the preparation of a crystallineDasatinib-(±)-1,2-butanediol solvate of Formula Ic, comprising thefollowing steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of suitable organic solvent and a suitable organic baseat a suitable temperature to obtain Formula I (In-situ)

treating the mass containing the Formula I (in-situ) with(=)-1,2-Butanediol at a suitable temperature, to obtain a crystallineDasatinib-(±)-1,2-butanediol solvate of Formula Ic,

Further, the present invention relates to the process for thepreparation of a crystalline Dasatinib-(±)-1,2-butanediol solvate ofFormula Ic, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding (±)-1,2-Butanediol    -   h) heating the reaction mass to a suitable temperature    -   i) maintaining the reaction mass at a suitable temperature    -   j) cooling the reaction mass to a suitable temperature    -   k) stirring the reaction mixture at a suitable temperature    -   l) filtering the reaction mixture under vacuum    -   m) suck drying the wet solid under vacuum    -   n) optionally washing with wet solid with as suitable organic        solvent    -   o) optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(±)-1,2-butanediol        solvate of Formula Ic.

Further according to step c), a suitable organic solvent is selectedfrom, Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferablyN,N-Dimethyl acetamide

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferably Diisopropylethylamineor Triethylamine, more preferably Triethylamine.

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 30 to 90° C., preferably 60 to 90°C., more preferably 83 to 87° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 30 to 122° C., preferably 90 to122° C., more preferably 118 to 122° C.

Further according to step j) and step k), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step o), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably 30 to 45° C., morepreferably 35 to 45° C.

Thirty second aspect of the present invention provides the crystallineDasatinib-(R)-1,2-Butanediol solvate.

Thirty third aspect of the present invention, the crystallinecrystalline Dasatinib-(R)-1,2-Butanediol solvate of Formula Id isfurther characterized by PXRD having the main 2-theta values 5.69±0.2,10.84±0.2, 11.30±0.2, 12.62±0.2, 13.45±0.2, 15.29±0.2, 17.15±0.2,17.35±0.2, 18.07±0.2, 18.23±0.2, 19.41±0.2, 20.64±0.2, 21.44±0.2,22.14±0.2, 23.90±0.2, 24.52±0.2, 25.97±0.2, 26.96±0.2, 27.19±0.2,27.66±0.2, 31.22±0.2, 32.53±0.2, 35.60±0.2, 37.42±0.2, 46.71±0.2 and thePXRD pattern in accordance with the FIG. 12.

TABLE 4 Num. Gonio d Int I/Imax  1  5.6994 15.494 449 100.0  2 10.84898.14843 87 19.3  3 11.3075 7.81901 268 59.8  4 12.6216 7.00769 197 44.0 5 13.4568 6.57462 62 13.8  6 15.2976 5.78736 59 13.2  7 17.1589 5.16353185 41.3  8 17.3559 3.10536 260 58.0  9 18.0714 4.90481 82 18.3 1018.2353 4.8611 111 24.8 11 19.4145 4.56842 36 8.1 12 20.6469 4.29842 388.4 13 21.4450 4.14024 73 16.2 14 22.1425 4.01136 130 29.1 15 22.51743.94541 117 26.0 16 23.9075 3.71906 126 28.2 17 24.5281 3.62635 44 9.918 25.9746 3.42759 56 12.5 19 25.9674 3.30361 103 23.0 20 27.19083.27698 92 20.5 21 27.6631 3.22209 67 15.0 22 31.2182 2.86279 32 7.1 2332.5391 2.74954 37 8.3 24 35.6055 2.51945 24 5.3 25 37.4285 2.40082 316.9 26 46.7133 1.94298 21 4.6

Thirty fourth aspect of the present invention, the crystallinecrystalline Dasatinib-(R)-1,2-Butanediol solvate of Formula Id isfurther characterized by DSC having endotherms at around 156.6 & 286.6°C. and the DSC pattern in accordance with the FIG. 11.

Thirty fifth aspect of the present invention provides a process for thepreparation of a crystalline Dasatinib-(R)-1,2-butanediol solvate ofFormula Id, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and (R)-1,2-butanediol anda suitable organic base at suitable temperature, to obtain a crystallineDasatinib-(R)-1,2-butanediol solvate of Formula Id,

Further, the present invention relates to the process for thepreparation of a crystalline Dasatinib-(R)-1,2-butanediol solvate ofFormula Id, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) optionally adding a suitable organic solvent and adding        (R)-1,2-butanediol    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) cooling the reaction mass to a suitable temperature    -   h) stirring the reaction mixture at a suitable temperature    -   i) filtering the reaction mixture under vacuum    -   j) suck drying the wet solid under vacuum    -   k) optionally washing with wet solid with a suitable organic        solvent    -   l) optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(R)-1,2-Butanediol        solvate of Formula Id

Further according to step c), a suitable organic solvent is selectedfrom, Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferablyN,N-Dimethyl acetamide

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 90 to 122° C., preferably 100 to122° C., more preferably 118 to 122° C.

Further according to step g) and step h), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step k), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably hydrocarbon solvent, more preferably Toluene.

Further according to step l), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably 30 to 45° C., morepreferably 35 to 45° C.

Thirty sixth aspect of the present invention provides an alternateprocess for the preparation of a crystallineDasatinib-(R)-1,2-Butanediol solvate of Formula Id, comprising thefollowing steps,

Treating the Dichloro intermediate of Formula II

with 2-piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and a suitable organicbase at a suitable temperature to obtain Formula I (In-situ)

treating the mass containing the Formula I with (R)-1,2-Butanediol at asuitable temperature, to obtain crystalline Dasatinib-(R)-1,2-butanediolsolvate of Formula Id,

Further, the present invention relates to the process for thepreparation of a crystalline Dasatinib-(R)-1,2-butanediol solvate ofFormula Id, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) optionally addition suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding (R)-1,2-Butanediol at a suitable temperature    -   h) heating the reaction mass to a suitable temperature    -   i) maintaining the reaction mass at a suitable temperature    -   j) cooling the reaction mass to a suitable temperature    -   k) stirring the reaction mixture at a suitable temperature    -   l) filtering the reaction mixture under vacuum    -   m) suck drying the wet solid under vacuum    -   n) optionally washing with wet solid with as suitable organic        solvent    -   o) optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(R)-1,2-butanediol        solvate of Formula Id

Further according to step c), a suitable organic solvent is selectedfrom Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferably N,N-Dimethylacetamide

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferably Diisopropylethylamineor Triethylamine, more preferably Triethylamine.

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 30 to 90° C., preferably 60 to 90°C., more preferably 83 to 87° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 30 to 122° C., preferably 90 to122° C., more preferably 118 to 122° C.

Further according to step j) and step k), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step o), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably 30 to 45° C., morepreferably 35 to 45° C.

Thirty seventh aspect of the present invention provides crystallineDasatinib-(S)-1,2-Butanediol solvate.

Thirty eighth aspect of the present invention, the crystallinecrystalline Dasatinib-(S)-1,2-Butanediol solvate of Formula Ie isfurther characterized by PXRD having the main 2-theta values 5.56±0.2,8.10±0.2, 10.75±0.2, 11.18±0.2, 12.39±0.2, 13.34±0.2, 14.43±0.2,15.07±0.2, 16.81±0.2, 17.12±0.2, 17.45±0.2, 18.02±0.2, 19.21±0.2,19.61±0.2, 20.10±0.2, 20.43±0.2, 21.24±0.2, 21.89±0.2, 22.30±0.2,23.70±0.2, 24.35±0.2, 25.07±0.2, 25.82±0.2, 26.72±0.2, 27.12±0.2,27.45±0.2, 30.99±0.2, 32.33±0.2, 34.97±0.2, 35.52±0.2, 37.39±0.2,40.97±0.2, 43.64±0.2, 46.54±0.2 and the PXRD pattern in accordance withthe FIG. 13.

TABLE 5 Num. Gonio d Int I/Imax  1  5.5632 15.8729 1345 100.0  2  8.102310.9035 33 2.4  3 10.7531 8.22083 144 10.7  4 11.1800 7.90788 623 46.3 5 12.3993 7.13285 229 17.0  6 13.3473 6.62829 108 8.0  7 14.43906.12952 38 2.9  8 15.0774 5.87136 85 6.3  9 16.8152 5.26829 183 13.6 1017.1202 5.17512 319 23.8 11 17.4552 5.17653 76 5.6 12 18.0232 4.91781142 10.6 13 19.2158 4.61522 38 2.8 14 19.6114 4.52298 28 2.1 15 20.10174.41378 31 2.3 16 20.4359 4.34234 44 3.2 17 21.2468 4.1784 97 7.2 1821.8969 4.0558 166 12.4 19 22.3074 3.98208 153 11.4 20 23.7051 3.75035161 11.9 21 24.3576 3.65135 41 3.0 22 35.0753 3.54844 35 2.6 23 25.80293.44765 58 4.3 24 26.7244 3.33311 96 7.1 25 27.1240 3.2849 98 7.3 2627.4580 3.24569 88 6.6 27 30.9917 2.88319 42 3.1 28 32.3337 2.76653 403.0 29 34.9751 2.56341 25 1.9 30 35.6234 2.52509 25 1.9 31 37.39633.40281 29 2.1 32 40.9758 2.2008 33 2.5 33 43.6448 2.0722 20 1.5 3446.5436 1.94966 23 1.7

Thirty ninth aspect of the present invention provides for a process forthe preparation of a crystalline Dasatinib-(S)-1,2-butanediol solvate ofFormula Ie, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and (S)-1,2-Butanediol anda suitable organic base at suitable temperature, to obtain crystallineDasatinib-(S)-1,2-butanediol solvate of Formula Ie,

Further, the present invention relates to a process for the preparationof a crystalline Dasatinib-(S)-1,2-butanediol solvate of Formula Ie,further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula II    -   c) optionally adding a suitable organic solvent and adding        (S)-1,2-butanediol    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) cooling the reaction mass to a suitable temperature    -   h) stirring the reaction mixture at a suitable temperature    -   i) filtering the reaction mixture under vacuum    -   j) suck drying the wet solid under vacuum    -   k) optionally washing with wet solid with a suitable organic        solvent    -   l) optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(S)-1,2-Butanediol        solvate of Formula Ie

Further according to step c), a suitable organic solvent is selectedfrom, Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferablyN,N-Dimethyl acetamide

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 90 to 120° C., preferably 100 to120° C., more preferably 110 to 120° C.

Further according to step g) and step h), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step k), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step l), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably 30 to 45° C., morepreferably 35 to 45° C.

Fortieth aspect of the present invention provides for an alternateprocess for the preparation of a crystallineDasatinib-(S)-1,2-butanediol solvate of Formula Ie, comprising thefollowing steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of suitable organic solvent and a suitable organic baseat a suitable temperature to obtain Formula I (In-situ)

treating the mass containing the Formula I (in-situ) with(S)-1,2-Butanediol at a suitable temperature, to obtain crystallineDasatinib-(S)-1,2-butanediol solvate of Formula Ie,

Further, the present invention relates to a process for the preparationof a crystalline Dasatinib-(S)-1,2-butanediol solvate of Formula Ie,further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) optionally addition suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding (S)-1,2-Butanediol at a suitable temperature    -   h) heating the reaction mass to a suitable temperature    -   i) maintaining the reaction mass at a suitable temperature    -   j) cooling the reaction mass to a suitable temperature    -   k) stirring the reaction mixture at a suitable temperature    -   l) filtering the reaction mixture under vacuum    -   m) suck drying the wet solid under vacuum    -   n) optionally washing with wet solid with as suitable organic        solvent    -   o) optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(S)-1,2-butanediol        solvate of Formula Ie.

Further according to step c), a suitable organic solvent is selectedfrom, Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferablyN,N-Dimethyl acetamide

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferably Diisopropylethylamineor Triethylamine, more preferably Triethylamine.

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 30 to 90° C., preferably 60 to 90°C., more preferably 83 to 87° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 30 to 122° C., preferably 90 to122° C., more preferably 118 to 122° C.

Further according to step j) and step k), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step o), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably, 30 to 45° C., morepreferably 35 to 45° C.

Forty first aspect of the present invention provides crystalline2,3-Butanediol solvate.

Forty second aspect of the present invention, the crystallinecrystalline Dasatinib-(±)-2, 3-Butanediol solvate of Formula Ig isfurther characterized by PXRD having the main 2-theta values 4.56±0.2,5.67±0.2, 6.76±0.2, 8.13±0.2, 10.35±0.2, 11.35±0.2, 12.50±0.2,13.09±0.2, 13.51±0.2, 14.26±0.2, 14.50±0.2, 15.30±0.2, 16.37±0.2,16.70±0.2, 17.06±0.2, 17.29±0.2, 17.87±0.2, 19.15±0.2, 19.42±0.2,20.02±0.2, 20.45±0.2, 20.80±0.2, 21.91±0.2, 22.97±0.2, 23.02±0.2,23.53±0.2, 25.25±0.2, 26.16±0.2, 26.49±0.2, 27.2±00.2, 27.61±0.2,27.95±0.2, 28.59±0.2, 30.36±0.2, 30.91±0.2, 31.43±0.2, 32.52±0.2,32.99±0.2, 33.8±0.2, 33.98±0.2, 34.69±0.2, 35.20±0.2, 36.17±0.2,36.52±0.2, 37.16±0.2, 37.79±0.2, 38.85±0.2, 39.81±0.2, 40.09±0.2,40.92±0.2, 41.49±0.2, 43.34±0.2, 44.04±0.2, 44.36±0.2, 44.70±0.2,45.76±0.2, 46.55±0.2, 47.18±0.2, 47.96±0.2, 49.11±0.2 and the PXRDpattern in accordance with the FIG. 16.

TABLE 6 Num. Gonio d Int I/Imax  1 4.5621 19.3538 1218 2.6  2 5.673315.5651 46723 100.0  3 6.7626 13.0603 1089 2.3  4 8.1329 10.8626 724 1.5 5 10.3500 8.54012 3819 8.2  6 11.3547 7.78657 26911 57.6  7 12.50477.07295 4435 9.5  8 13.0944 6.75574 3581 7.7  9 13.5166 6.54567 827 1.810 14.2635 6.20451 1168 2.5 11 14.5064 6.10118 759 1.6 12 15.30385.78503 1639 3.5 13 16.3767 5.40835 1053 2.3 14 16.7036 5.30325 1037 2.215 17.0649 5.19175 8366 17.9 16 17.2983 5.12223 9241 19.8 17 17.87474.95834 3837 8.2 18 19.1544 4.62986 994 2.1 19 19.4242 4.56617 584 1.320 20.0226 4.43103 1051 2.2 21 20.4515 4.33907 3340 7.1 22 20.80894.26534 666 1.4 23 21.9156 4.05237 4479 9.6 24 22.2790 3.98709 2903 6.225 23.0271 3.85923 2940 6.3 26 23.5386 3.77651 1052 2.3 27 25.25433.5237 1587 3.4 28 26.1681 3.40269 3851 8.2 29 26.4970 3.36119 1815 3.930 27.2053 3.27526 1785 3.8 31 27.6110 3.22805 2417 5.2 32 27.95423.18919 929 2.0 33 28.5974 3.11892 560 1.2 34 30.3668 2.94109 576 1.2 3530.9190 2.88981 511 1.1 36 31.4393 2.84317 1342 2.9 37 32.5271 2.750521203 2.6 38 32.9934 2.7127 516 1.1 39 33.8802 2.64978 581 1.2 40 33.98102.63609 562 1.2 41 34.6907 2.58377 595 1.3 42 35.2088 2.54692 529 1.1 4336.1707 2.48137 550 1.2 44 36.5245 2.45814 455 1.0 45 37.1603 2.41753512 1.1 46 37.7906 2.37865 577 1.2 47 38.8510 2.31613 458 1.0 48 39.81562.26221 670 1.4 49 40.0922 2.24724 595 1.3 50 40.9296 2.20318 448 1.0 5141.4902 2.17469 655 1.4 52 43.3423 2.08596 382 0.8 53 44.0184 2.05414491 1.1 54 44.3676 2.0401 422 0.9 55 44.7003 2.02569 414 0.9 56 45.76541.98099 402 0.9 57 46.5583 1.94908 394 0.8 58 47.1824 1.92475 406 0.9 5947.9681 1.89504 403 0.9 60 49.1109 1.85358 359 0.8

Forty third aspect of the present invention, the crystalline crystallineDasatinib-(±)-2, 3-Butanediol solvate of Formula Ig is furthercharacterized by DSC having endotherms at around 171.2 & 284.6° C. andthe DSC pattern in accordance with the FIG. 15.

Forty fourth aspect of the present invention provides for thepreparation of a crystalline Dasatinib-(±)-2,3-butanediol solvate ofFormula Ig, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and (±)-2,3-Butanediol anda suitable organic base at suitable temperature, to obtain a crystallineDasatinib-(±)-2,3-butanediol solvate of Formula I,

Further, the present invention relates to a process for the preparationof crystalline Dasatinib-(±)-2,3-butanediol solvate of Formula Ig,further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) optionally adding a suitable organic solvent and adding a        (±)-2,3-butanediol    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) cooling the reaction mass to a suitable temperature    -   h) stirring the reaction mixture at a suitable temperature    -   i) filtering the reaction mixture under vacuum    -   j) suck drying the wet solid under vacuum    -   k) optionally washing with wet solid with a suitable organic        solvent    -   l) optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(±)-2,3-butanediol        solvate of Formula Ig.

Further according to step c), a suitable organic solvent is selectedfrom, Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferablyN,N-Dimethyl acetamide

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 90 to 120° C., preferably 100 to120° C., more preferably 110 to 120° C.

Further according to step g) and step h), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably 50 to 65°C., more preferably 55 to 65° C.

Further according to step k), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solvents,preferably hydrocarbon solvent, more preferably Toluene.

Further according to step l), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably 30 to 45° C., morepreferably 35 to 45° C.

Forty fifth aspect of the present invention provides an alternateprocess for the preparation of a crystallineDasatinib-(±)-2,3-butanediol solvate of Formula Ig comprising thefollowing steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of suitable organic solvent and a suitable organic baseat a suitable temperature to obtain Formula I (In-situ)

treating the mass containing the Formula I (in-situ) with(=)-2,3-Butanediol at a suitable temperature, to obtain a crystallineDasatinib-(±)-2,3-butanediol solvate of Formula I.

Further, the present invention relates to an alternate process for thepreparation of a crystalline Dasatinib-(±)-2,3-butanediol solvate ofFormula Ig, comprising the following steps,

-   -   a) Charging Dichloro intermediate of Formula II into a reactor    -   b) Adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) Adding a suitable organic solvent    -   d) Optionally addition suitable organic base    -   e) Heating the reaction mass to a suitable temperature    -   f) Maintaining the reaction mass at a suitable temperature    -   g) Adding (±)-2,3-Butanediol at a suitable temperature    -   h) Heating the reaction mass to a suitable temperature    -   i) Maintaining the reaction mass at a suitable temperature    -   j) Cooling the reaction mass to a suitable temperature    -   k) Stirring the reaction mixture at a suitable temperature    -   l) Filtering the reaction mixture under vacuum    -   m) Suck drying the wet solid under vacuum    -   n) Optionally washing with wet solid with as suitable organic        solvent    -   o) Optionally drying the wet solid at a suitable temperature        under vacuum to obtain crystalline Dasatinib-(±)-2,3-butanediol        solvate of Formula Ig.

Further according to step c), a suitable organic solvent is selectedfrom, Dimethyl sulfoxide, N,N-Dimethyl acetamide, preferablyN,N-Dimethyl acetamide

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferably Diisopropylethylamineor Triethylamine, more preferably Triethylamine.

Further according to step e) and step f), a suitable temperature isselected from the range consisting of 30 to 90° C., preferably, 60 to90° C., more preferably 83 to 87° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 30 to 122° C., preferably, 90 to122° C., more preferably 118 to 122° C.

Further according to step j) and step k), a suitable temperature isselected from the range consisting of 30 to 65° C., preferably, 50 to65° C., more preferably 63 to 65° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solventspreferably, hydrocarbon solvent, more preferably Toluene.

Further according to step o), a suitable temperature is selected fromthe range consisting of 20 to 45° C., preferably, 30 to 45° C., morepreferably 35 to 45° C.

Forty sixth aspect of the present invention provides a process for thepreparation of Amorphous Dasatinib of Formula I, comprising thefollowing steps,

Treating the Dichloro intermediate of Formula II

with 2(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and a suitable organicbase at a suitable temperature to obtain Dasatinib of Formula I(in-situ)

followed by treating the reaction mass with a suitable Butanediol toobtain a crystalline Dasatinib-Butanediol solvate of Formula Ic orFormula Id or Formula Ie or Formula Ig,

Wherein, Butanediol=(±)-1,2-Butane diol or (R)-1,2-Butanediol or(S)-1,2-Butanediol or (±)-2,3-Butanediol

Formula Ic=Dasatinib-(±)-1,2-Butane diol solvate

Formula Id=Dasatinib-(R)-1,2-Butanediol solvate

Formula Ie=Dasatinib-(S)-1,2-Butanediol solvate

Formula Ig=Dasatinib-(±)-2,3-Butane diol solvate

Treating a crystalline Dasatinib-Butanediol solvate of Formula I orFormula Id or Formula Ie or Formula Ig in a suitable acid aq. solutionand treating with aq. Ammonia solution to obtain Amorphous Dasatinib ofFormula I

Further, the present invention relates to a process for the preparationof Amorphous Dasatinib of Formula I, further comprising the followingsteps,

-   -   a) Charging Dichloro intermediate of Formula II into a reactor    -   b) Adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) Adding a suitable organic solvent    -   d) Optionally adding a suitable organic base    -   e) Heating the reaction mass to a suitable temperature    -   f) Maintaining the reaction mass at a suitable temperature    -   g) Adding suitable Butanediol at a suitable temperate    -   h) Heating the reaction mass to a suitable temperature    -   i) Maintaining the reaction mass at a suitable temperature    -   j) Cooling the reaction mass to a suitable temperature    -   k) Stirring the reaction mixture at a suitable temperature    -   l) Filtering the reaction mixture under vacuum    -   m) Suck drying the wet solid under vacuum    -   n) Optionally washing with wet solid with as suitable organic        solvent    -   o) Optionally drying the wet solid    -   p) Contacting the wet solid of Dasatinib-Butanediol solvate of        Formula Ic or Formula Id or Formula Ie or Formula Ig with a        suitable acid and water at a suitable temperature    -   q) Cooling the mass to a suitable temperature    -   r) Treating the mass with aq. Ammonia solution at suitable        temperature    -   s) Warming the mass to a suitable temperature    -   t) Maintaining the mass at suitable temperature    -   u) Filtering and washing the wet solid with water    -   v) Drying the wet solid at a suitable temperature under vacuum        to obtain Amorphous Dasatinib of Formula I

Further according to step c), a suitable organic solvent is selectedfrom the group consisting of Sulfoxide, Amide solvents, preferablyDimethyl sulfoxide, N,N-Dimethyl acetamide, more preferably N,N-Dimethylacetamide.

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferablyN,N-Diisopropylethylamine, Triethylamine, more preferably Triethylamine.

Further according to step e), step f) and step g) a suitable temperatureis selected from the range consisting of 30 to 90° C., preferably 80 to90° C., more preferably 83 to 87° C.

Further according to step g) suitable butanediol is selected from thegroup consisting of vicinal butanediol, more preferably isomer/isomericmixture of 2,3-Butanediol or isomer/isomeric mixture of 1,2-butanediol,most preferably (1)-1,2-Butanediol or (R)-1,2-Butanediol or(S)-1,2-Butanediol or (±)-2,3-Butanediol.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 90 to 122° C., preferably 100 to122° C., more preferably 118 to 122° C.

Further according to step j) and step k), a suitable temperature isselected from the range consisting of 30 to 67° C., preferably 50 to 67°C., more preferably 63 to 67° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solvents,preferably hydrocarbon solvent, more preferably Toluene.

Further according to step p), step s) and step t) a suitable temperatureis selected from the range consisting of 10 to 30° C., preferably 15 to20° C., more preferably 20 to 30° C.

Further according to step q) and step r) a suitable temperature isselected from the range consisting of 5 to 30° C., preferably 5 to 20°C., more preferably 5 to 15° C.

Further according to step v), a suitable temperature is selected fromthe range consisting of 30 to 60° C., preferably, 40 to 60° C., morepreferably 50 to 60° C.

The input for the process for the preparation of Amorphous Dasatinibaccording to one 30 aspect of present invention is a crystallineDasatinib-Butanediol solvate of Formula Ic or Formula Id or Formula Ieor Formula Ig preferably Dasatinib-(±)1,2-Butanediol solvate orcrystalline Dasatinib-(R)-1,2-Butanediol solvate or crystallineDasatinib-(S)-1,2-Butanediol solvate or crystallineDasatinib-(±)-2,3-Butanediol solvate. Wherein, Formula Ic isDasatinib-(±)-1,2-Butane diol solvate, Formula Id isDasatinib-(R)-1,2-Butanediol solvate, Formula Ie isDasatinib-(S)-1,2-Butanediol solvate, Formula Ig isDasatinib-(±)-2,3-Butane diol solvate.

Forty seventh aspect of the present invention provides a process for thepreparation of Amorphous Dasatinib, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and a suitable organicbase at a suitable temperature, to obtain a crystallineDasatinib-(±)-1,2-Butanediol solvate of Formula Ic,

treating a crystalline Dasatinib-(±)-1,2-Butanediol solvate of FormulaIc with a suitable acid aqueous solution and treating with aq. Ammoniasolution to obtain Amorphous Dasatinib.

Further, the present invention relates to a process for the preparationof Amorphous Dasatinib, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding (±)-1,2-Butanediol at a suitable temperate    -   h) heating the reaction mass to a suitable temperature    -   i) maintaining the reaction mass at a suitable temperature    -   j) cooling the reaction mass to a suitable temperature    -   k) stirring the reaction mixture at a suitable temperature    -   l) filtering the reaction mixture under vacuum    -   m) suck drying the wet solid under vacuum    -   n) optionally washing the wet solid with as suitable organic        solvent    -   o) optionally drying the wet solid    -   p) Contacting the wet solid of Dasatinib-(±)-1,2-Butanediol        solvate of Formula Ie with water and citric acid at a suitable        temperature    -   q) cooling the mass to a suitable temperature    -   r) treating the mass with aq. Ammonia solution at suitable        temperature    -   s) warming the mass to a suitable temperature    -   t) maintaining the mass at suitable temperature    -   u) filtering and washing the wet solid with water    -   v) drying the wet solid at a suitable temperature under vacuum        to obtain Amorphous Dasatinib.

Further according to step c), a suitable organic solvent is selectedfrom the group consisting of Sulfoxide, Amide solvents, preferablyDimethyl sulfoxide, N,N-Dimethyl acetamide, more preferably N,N-Dimethylacetamide.

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferablyN,N-Diisopropylethylamine, Triethylamine, more preferably Triethylamine.

Further according to step e), step f) and step g) a suitable temperatureis selected from the range consisting of 30 to 90° C., preferably 80 to90° C., more preferably 83 to 87° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 90 to 122° C., preferably 100 to122° C., more preferably 118 to 122° C.

Further according in step j) and step k), a suitable temperature isselected from the range consisting of 30 to 67° C., preferably 50 to 67°C., more preferably 63 to 67° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solvents,preferably hydrocarbon solvent, more preferably Toluene.

Further according to step p), step s) and step t) a suitable temperatureis selected from the range consisting of 10 to 30° C., preferably 15 to20° C., more preferably 20 to 30° C.

Further according to step q) and step r) a suitable temperature isselected from the range consisting of 5 to 30° C., preferably 5 to 20°C., more preferably 5 to 15° C.

Further according to step v), a suitable temperature is selected fromthe range consisting of 30 to 60° C., preferably 40 to 60° C., morepreferably 50 to 60° C.

According to the one of the aspects of present invention the input forthe process for the preparation of Amorphous Dasatinib isDasatinib-(±)1,2-Butanediol solvate

Forty eighth aspect of the present invention provides a process for thepreparation of Amorphous Dasatinib, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and a suitable organicbase at a suitable temperature, to obtain crystallineDasatinib-(R)-1,2-Butanediol solvate of Formula Id,

Contacting a crystalline Dasatinib-(R)-1,2-Butanediol solvate of FormulaId with a suitable acid aqueous solution, treating with Aq. Ammoniasolution to obtain Amorphous Dasatinib.

Further, the present invention relates to a process for the preparationof Amorphous Dasatinib, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding (R)-1,2-Butanediol at a suitable temperate    -   h) heating the reaction mass to a suitable temperature    -   i) maintaining the reaction mass at a suitable temperature    -   j) cooling the reaction mass to a suitable temperature    -   k) stirring the reaction mixture at a suitable temperature    -   l) filtering the reaction mixture under vacuum    -   m) suck drying the wet solid under vacuum    -   n) optionally washing with wet solid with as suitable organic        solvent    -   o) optionally drying the wet solid    -   p) contacting the wet solid of Dasatinib-(R)-1,2-Butanediol        solvate of Formula Id with water and citric acid at suitable        temperature    -   q) cooling the mass to a suitable temperature    -   r) treating the mass with aq. Ammonia solution at suitable        temperature    -   s) warning the mass to a suitable temperature    -   t) maintaining the mass at suitable temperature    -   u) filtering and washing the wet solid with water    -   v) drying the wet solid at a suitable temperature under vacuum        to obtain Amorphous Dasatinib.

Further according to step c), a suitable organic solvent is selectedfrom the group consisting of Sulfoxide, Amide solvents, preferablyDimethyl sulfoxide, N,N-Dimethyl acetamide, more preferably N,N-Dimethylacetamide.

Further according to step d), a suitable organic base is selected fromthe group consisting of tertiary amine, preferablyN,N-Diisopropylethylamine, Triethylamine, more preferably Triethylamine.

Further according to step e), step f) and step g) a suitable temperatureis selected from the range consisting of 30 to 90° C., preferably 80 to90° C., more preferably 83 to 87° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 90 to 122° C., preferably 100 to122° C., more preferably 118 to 122° C.

Further according to step j) and step k), a suitable temperature isselected from the range consisting of 30 to 67° C., preferably 50 to 67°C., more preferably 63 to 67° C.

Further according to step n), a suitable organic solvent is selectedfrom the group consisting of Ether solvents, Hydrocarbon solvents,preferably hydrocarbon solvent, more preferably Toluene.

Further according to step p), step s) and step t) a suitable temperatureis selected from the range consisting of 10 to 30° C., preferably 15 to20° C., more preferably 20 to 30° C.

Further according to step q) and step r) a suitable temperature isselected from the range consisting of 5 to 30° C., preferably 5 to 20°C., more preferably 5 to 15° C.

Further according to step v), a suitable temperature is selected fromthe range consisting of 30 to 60° C., preferably 40 to 60° C. morepreferably 50 to 60° C.

Forty ninth aspect of the present invention provides a process for thepreparation of Amorphous Dasatinib, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and a suitable organicbase at a suitable temperature, to obtain a crystallineDasatinib-(S)-1,2-Butanediol solvate of Formula Ie,

treating a crystalline Dasatinib-(S)-1,2-Butanediol solvate of FormulaIe with a suitable acid aqueous solution, treating with aq. Ammoniasolution to obtain Amorphous Dasatinib

Further, the present invention relates to a process for the preparationof Amorphous Dasatinib, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding (S)-1,2-Butanediol at a suitable temperate    -   h) heating the reaction mass to a suitable temperature    -   i) maintaining the reaction mass at a suitable temperature    -   j) cooling the reaction mass to a suitable temperature    -   k) stirring the reaction mixture at a suitable temperature    -   l) filtering the reaction mixture under vacuum    -   m) suck drying the wet solid under vacuum    -   n) optionally washing with wet solid with as suitable organic        solvent    -   o) optionally drying the wet solid    -   p) contacting the wet solid of Dasatinib-(S)-1,2-Butanediol        solvate of Formula Ie with water and citric acid at suitable        temperature    -   q) cooling the mass to a suitable temperature    -   r) treating the mass with aq. Ammonia solution at suitable        temperature    -   s) warming the mass to a suitable temperature    -   t) maintaining the mass at suitable temperature    -   u) filtering and washing the wet solid with water    -   v) drying the wet solid at a suitable temperature under vacuum        to obtain Amorphous Dasatinib.

Fiftieth aspect of the present invention provides a process for thepreparation of Amorphous Dasatinib, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent and a suitable organicbase at a suitable temperature, to obtain a crystallineDasatinib-(±)-2,3-Butanediol solvate of Formula Ig,

treating crystalline Dasatinib-(±)-2,3-Butanediol solvate of Formula Igwith a suitable acid aqueous solution, treating with aq. Ammoniasolution to obtain Amorphous Dasatinib

Further, the present invention relates to a process for the preparationof Amorphous Dasatinib, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) optionally adding a suitable organic base    -   e) heating the reaction mass to a suitable temperature    -   f) maintaining the reaction mass at a suitable temperature    -   g) adding (±)-2,3-Butanediol at a suitable temperate    -   h) heating the reaction mass to a suitable temperature    -   i) maintaining the reaction mass at a suitable temperature    -   j) cooling the reaction mass to a suitable temperature    -   k) stirring the reaction mixture at a suitable temperature    -   l) filtering the reaction mixture under vacuum    -   m) suck drying the wet solid under vacuum    -   n) optionally washing with wet solid with as suitable organic        solvent    -   o) optionally drying the wet solid    -   p) contacting the wet solid of Dasatinib-(±)-2,3-Butanediol        solvate of Formula Ig with water and citric acid at suitable        temperature    -   q) cooling the mass to a suitable temperature    -   r) treating the mass with aq.Ammonia solution at suitable        temperature    -   s) warming the mass to a suitable temperature    -   t) maintaining the mass at suitable temperature    -   u) filtering and washing the wet solid with water    -   v) drying the wet solid at a suitable temperature under vacuum        to obtain Amorphous Dasatinib.

Fifty first aspect of the present invention provides a process for thepreparation of Anhydrous Dasatinib, comprising the following steps,

Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent at a suitable temperature,to obtain crystalline Anhydrous Dasatinib.

Further, the present invention relates to a process for the preparationof Anhydrous Dasatinib, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) heating the reaction mass to a suitable temperature    -   e) maintaining the reaction mass at a suitable temperature    -   f) adding a suitable organic solvent at a suitable temperate    -   g) maintaining the reaction mass at a suitable temperature    -   h) cooling the reaction mass to a suitable temperature    -   i) stirring the reaction mixture at a suitable temperature    -   j) filtering the reaction mixture under vacuum    -   k) washing with wet solid with as suitable organic solvent    -   l) suck drying the wet solid under vacuum    -   m) drying the wet solid at a suitable temperature under vacuum        to obtain Anhydrous Dasatinib.

Further according to step c), step f) and step k), a suitable organicsolvent is selected from the group consisting Alcohol solvents,preferably Methanol

Further according to step d), step e), step f) and step g), a suitabletemperature is selected from the range consisting of 50 to 69° C.,preferably 60 to 69° C., more preferably 65 to 69° C.

Further according to step h) and step i), a suitable temperature isselected from the range consisting of 5 to 30° C., preferably 10 to 30°C., more preferably 20 to 30° C.

Further according to step m), a suitable temperature is selected fromthe range consisting of 30 to 60° C., preferably 40 to 60° C., morepreferably 50 to 60° C.

Fifty second aspect of the present invention provides a process for thepreparation of Dasatinib Monohydrate,

The process for the preparation of Dasatinib Monohydrate, comprising thefollowing steps, Treating the Dichloro intermediate of Formula II

with 2-(piperazin-1-yl)ethan-1-ol of Formula III

in the presence of a suitable organic solvent at a suitable temperature,to obtain crystalline Anhydrous Dasatinib,

Treating Anhydrous Dasatinib with suitable solvent(s) at a suitabletemperature to obtain Dasatinib Monohydrate.

Further, the present invention relates to a process for the preparationof Anhydrous Dasatinib, further comprising the following steps,

-   -   a) charging Dichloro intermediate of Formula II into a reactor    -   b) adding 2-(piperazin-1-yl)ethan-1-ol of Formula III    -   c) adding a suitable organic solvent    -   d) heating the reaction mass to a suitable temperature    -   e) maintaining the reaction mass at a suitable temperature    -   f) adding a suitable organic solvent at a suitable temperate    -   g) maintaining the reaction mass at a suitable temperature    -   h) cooling the reaction mass to a suitable temperature    -   i) stirring the reaction mixture at a suitable temperature    -   j) filtering the reaction mixture under vacuum    -   k) washing the wet solid with as suitable organic solvent    -   l) suck drying the wet solid under vacuum    -   m) drying the wet solid at a suitable temperature under vacuum        to obtain Anhydrous Dasatinib    -   n) Treating the Anhydrous Dasatinib with suitable solvent(s) at        a suitable temperature    -   o) maintaining the reaction mass at a suitable temperature    -   p) cooling the mass to a suitable temperature    -   q) maintaining the reaction mass at a suitable temperature    -   r) filtering and washing the wet solid with suitable solvent    -   s) drying the wet solid at a suitable temperature under vacuum        to obtain Dasatinib Monohydrate.

Further according to step c), step f) and step k), a suitable organicsolvent is selected from the group consisting Alcohol solvents,preferably Methanol.

Further according to step d), step e), step f) and step g), a suitabletemperature is selected from the range consisting of 50 to 69° C.,preferably 60 to 69° C., more preferably 65 to 69° C.

Further according to step h), step i), step p) and step q), a suitabletemperature is selected from the range consisting of 5 to 30° C.,preferably 10 to 30° C., more preferably 20 to 30° C.

Further according to step m) and step s), a suitable temperature isselected from the range consisting of 30 to 60° C., preferably 40 to 60°C., more preferably 50 to 60° C.

Further according to step n) and step o), a suitable temperature isselected from the range consisting of 50 to 90° C., preferably 60 to 90°C., more preferably 80 to 90° C.

Accordingly, the different crystalline Dasatinib forms of the presentinvention are prepared and characterised by orthogonal analytical tools.

Characterization Techniques:

FT-IR, DSC, 1H NMR and PXRD techniques were used for characterising theco-crystal. The infrared spectroscopy, presents a great quantity ofinformation about the chemical bonds and interaction. It is a fastanalysis method, non-destructive.

The Powder X-ray diffraction is one of the most used techniques todetermine different crystalline structures. This technique candistinguish the presence of a new crystallographic motif, which can be apolymorph or a co-crystal. It is a non-destructive method and presentsdiffractions patterns unique for each structure.

The differential scanning calorimetry is a characterization method basedon the heat of reaction involved in different thermal events. For thepharmaceutical industry, the DSC is mostly used to obtain melting pointsof the API and thus, determine its purity. For the co-crystal analysis,there is a clear difference between the melting point of the co-formerand the co-crystal itself.

Instrumental Parameters:

The ¹H-NMR spectrum recorded in Bruker 400 MHz spectrometer usingDMSO-d6 as solvent and chemical shifts are reported in ppm downfieldfrom TMS.

DSC was performed on a Discovery DSC (TA instruments). About 3-5 mg ofsample placed in crimped aluminium sample pan to be positioned on autosampler. The temperature range was from 30-350 OC @ 10° C./min. Sampleswere purged by a stream of nitrogen flowing at 50 mL/min.

Equilibrate: 30° C.

Ramp: 10° C./min

Range: 30° C.-350° C.

The FT-IR spectrum (Fourier transform R spectroscopy) was recorded usingthe Fisher Scientific (NICOLET-iS50-FTIR), equipped with a KBr splitterand a DTGS KBr detector. The spectrum was recorded in the range of 4000cm−1 to 400 cm−1

The powder X-ray powder diffractogram (XRPD) was obtained by using theinstrument XRD BRUKER D8 ADVANCE, equipped with LYNXEYE detector with 40mA current intensity and 40 kV voltage.

The sample was arranged on a Si-Zero background Sample holder andanalysed using the following parameters:

-   -   Scanning range (°): 3.000 to 60.000    -   Step size (°): 0.03    -   Scan type: Locked coupled    -   Scanning mode: continuous    -   Count time per step (s): 0.5    -   Delay time (s): 0    -   Divergent slit: 0.300    -   Antiscatter slit: 0.300

Advantages of Present Invention

An API can exist in a variety of solid state forms, which include:polymorphs; solvates; hydrates, salts; co-crystals and amorphous forms.Each form exhibits unique physiochemical properties that can profoundlyinfluence the bioavailability, stability, manufacturability and otherperformance characteristics of the Formulated API.

Crystalline forms when compared to the amorphous form often show desiredunique physical and/or biological characteristics which usuallycontributes in the manufacture or Formulation of the active compound, tothe purity levels and uniformity required for regulatory approval.Hence, it is desirable to provide the pharmaceutically active ingredientin a substantially pure, crystalline and stable form of API.

Furthermore, the provision of further crystalline forms of apharmaceutically useful compound offers an opportunity to improve theperformance profile of a pharmaceutical product. In particular, not allsolid forms of a pharmaceutically useful compound are equally suited fordevelopment of a pharmaceutical dosage form. It is therefore desirableto widen the reservoir of materials a Formulation scientist can selectfrom, such that he can design a new dosage form of a drug havingimproved characteristics.

In simple terms, Co-crystals are an important class of pharmaceuticalmaterials that can enhance solubility and dissolution by forming acrystal of a drug and other benign molecule or co-former with specificstoichiometric compositions.

According to Almarsson and Zaworotko the definition of pharmaceuticalco-crystals-co-crystals are those that are formed between an activepharmaceutical ingredient (API) and a co-crystal former (CF), which is asolid under ambient conditions, and is not limited to two components.The components of the crystal interact by hydrogen bond or othernoncovalent and non-ionic interactions (Ö. Almarsson, M. J. Zaworotko,“Crystal engineering of the composition of pharmaceutical phases. Dopharmaceutical co-crystals represent anew path to improved medicines?”Chem. Commun. 2004, 17, pp. 1889-1896).

Dasatinib is a drug with poor solubility in water. Hence, there exists areal need to improve the aqueous solubility of Dasatinib for betterbioavailability.

Generally, the poor solubility of drugs in water can be improved usingformation of their respective co-crystals (International Journal ofPharmaceutics. 2013, 453, 101).

The solution to the technical problem underlying the present inventionis the provision of a crystalline forms comprising Dasatinib-Thymineco-crystal, Dasatinib-Adenine co-crystal and the provision of processesfor obtaining the same.

In an endeavor to achieve stable crystalline co-crystals of Dasatinib,different co-formers have been screened. Co-formers have been selectedby keeping in mind the basicity of Dasatinib. Accordingly, Piperazine,Methyl paraben, Thymine & Adenine were attempted for co-crystalformation. However, our results indicated co-crystal formation withco-formers namely Thymine & Adenine. The crystalline co-crystal obtainedhas been characterized by orthogonal analytical tools namely 1H NMR.DSC, PXRD and FT-R.

It is therefore an object of the present invention to provide a highlyreproducible and economical process of providing Dasatinib-Thymineco-crystal of Formula Ia and Dasatinib-Adenine co-crystal of Formula Ibin substantially pure forms. Furthermore, it would be desirable toprovide crystalline solid forms of Dasatinib-Thymine co-crystal ofFormula Ia and Dasatinib-Adenine co-crystal of Formula Ib showingimproved physical and/or biological characteristics.

Advantages of Usage of Thymine & Adenine as Co-Formers

-   -   Thymine is one of the pyrimidine bases found in DNA and Adenine        is one of the purine bases found in DNA and is a constituent of        numerous coenzymes.    -   LD₅₀ value for thymine is 3500 mg/Kg (Organism: rat, Route:        oral) & LD₅₀ value for Adenine is 227 mg/Kg (Organism: rat,        Route: oral).    -   Both Thymine & Adenine are thermally stable (melting points of        both Thymine & Adenine are greater than 300° C.).    -   Both Thymine & Adenine are chemically stable.    -   Both Thymine & Adenine are non-hygroscopic.    -   Both Thymine & Adenine are easy to handle as they are a free        flowing powders.    -   Both Thymine & Adenine have availability of Hydrogen bond donors        and acceptors

Advantages of Dasatinib-Thymine & Dasatinib-Adenine Co-Crystals

-   -   Literature mentions about better solubility of anhydrous        Dasatinib (2.40 times) compared to Monohydrate form (Crys.        Growth Des. 2012, 12, 2122-2126). WO2013186726A2 mentions about        the advantages in solubility of dasatinib co-crystals over        Monohydrate and anhydrous forms.    -   Dasatinib-Thymine co-crystal & Dasatinib-Adenine co-crystals of        present invention have the considerably higher solubility in        water and aqueous buffer solution in comparison to the Dasatinib        Monohydrate.    -   The present invention relates to Dasatinib-Thymine co-crystal &        Dasatinib-Adenine co-crystals which has relatively less        hygroscopicity in comparison with the anhydrous Dasatinib.    -   The processes of the present invention for the formation of        co-crystals does not involve the need to use Dasatinib        monohydrate as the input material.    -   One of the processes of the present invention involves one-pot        synthesis of Dasatinib-Thymine co-crystal formation without the        isolation of Dasatinib as intermediate.    -   The processes of the present invention for the preparation of        Dasatinib-Thymine co-crystal & Dasatinib-Adenine co-crystals are        scale-up friendly.    -   The process of the present invention for the preparation of        Dasatinib-Thymine co-crystal & Dasatinib-Adenine co-crystals        does not involve the necessity of inert condition, hence        economical and easy to operate.    -   The process of the present invention does not involve additional        operations during workup such as layer separation and        evaporations hence economical, time saving and easy to operate.

Advantages of Dasatinib Butanediol Solvate

-   -   Economic and scalable process    -   Eco-friendly reagents and solvents are used    -   Direct isolation Dasatinib-Butanediol solvate without isolating        any solid form of Dasatinib    -   Usage of less volume (5.00 v) of butane diols for the formation        of Dasatinib-Butanediol solvate    -   Controlling the Dasatinib-N-oxide impurity without using any        antioxidants in the reaction    -   Direct isolation of substantially pure Dasatinib-Butanediol        solvate without any additional purification    -   Elimination of the laborious workup such us layer separation,        concentration, trituration and re-crystallisation etc.

Advantages of Process for Preparation of Dasatinib Amorphous Form fromButanediol Solvate

-   -   Economic and scalable process    -   Eco-friendly reagent and solvents are used    -   Direct isolation Amorphous Dasatinib without isolating any solid        form of Dasatinib    -   Usage of less volumes (around 5.00 to 10.0 v) of solvent for the        formation of Amorphous Dasatinib    -   Controlling the Dasatinib-N-oxide impurity without using any        antioxidants in the reaction    -   Isolation of substantially pure Amorphous Dasatinib without any        additional purification    -   Elimination of the laborious workup such us layer separation,        concentration, trituration and re-crystallisation etc.    -   Usage of mild organic acid (solid) and mild base for the        formation of Amorphous Dasatinib    -   reparation of Amorphous Dasatinib without isolation any acid        addition salts    -   Preparation procedure of Amorphous Dasatinib does not usage of        any polymers    -   Preparation procedure of Amorphous Dasatinib does not involve        the usage of special technologies like spray drying, ball        milling and etc.

The dasatinib process impurities well controlled by the presentinvention in a cost effective manner are as below.

BRIEF DESCRIPTION OF THE FIGURES

In order that the disclosure may be readily understood and put intopractical effect, reference will now be made to exemplary embodiments asillustrated with reference to the accompanying figures. The figurestogether with a detailed description below, are incorporated in and formpart of the specification, and serve to further illustrate theembodiments and explain various principles and advantages, in accordancewith the present disclosure wherein:

FIG. 1: Illustrates the ¹H NMR pattern of the crystallineDasatinib-Thymine co-crystal of Formula Ia.

FIG. 2: Illustrates the DSC thermogram of the crystallineDasatinib-Thymine co-crystal of Formula Ia.

FIG. 3: Illustrates the PXRD of crystalline the Dasatinib-Thymineco-crystal of Formula Ia.

FIG. 4: Illustrates the ¹H NMR pattern of the crystallineDasatinib-Adenine co-crystal of Formula Ib.

FIG. 5: Illustrates the DSC thermogram of the crystallineDasatinib-Adenine co-crystal of Formula Ib.

FIG. 6: Illustrates the PXRD of crystalline the Dasatinib-Adenineco-crystal of Formula Ib.

FIG. 7: Illustrates the ¹H NMR pattern of the crystallineDasatinib-(±)-1,2-Butanediol solvate of Formula Ic.

FIG. 8: Illustrates the DSC thermogram of the crystallineDasatinib-(±)-1,2-Butanediol solvate of Formula Ic.

FIG. 9: Illustrates the PXRD of crystalline theDasatinib-(±)-1,2-Butanediol solvate of Formula Ic.

FIG. 10: Illustrates the ¹H NMR pattern of the crystallineDasatinib-(R)-1,2-Butanediol solvate of Formula Id.

FIG. 11: Illustrates the DSC thermogram of the crystallineDasatinib-(R)-1,2-Butanediol solvate of Formula Id.

FIG. 12: Illustrates the PXRD of the crystallineDasatinib-(R)-1,2-Butanediol solvate of Formula Id.

FIG. 13: Illustrates the PXRD of the crystallineDasatinib-(S)-1,2-Butanediol solvate of Formula Ie.

FIG. 14: Illustrates the ¹H NMR pattern of the crystallineDasatinib-(±)-2,3-Butanediol solvate of Formula Ig.

FIG. 15: Illustrates the DSC thermogram of the crystallineDasatinib-(±)-2,3-Butanediol solvate of Formula Ig.

FIG. 16: Illustrates the PXRD of crystalline theDasatinib-(±)-2,3-Butanediol solvate of Formula Ig.

FIG. 17: Illustrates the PXRD of amorphous Dasatinib.

The method of analysis of the compounds represented in the figures asabove are as below:

PXRD Analysis

About 300 mg of powder sample was taken onto the sample holder and wastightly packed on the sample holder uniformly by means of glass slideand Powder X-ray diffraction was recorded on Bruker D8 Advancediffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation(λ=1.5406 Å) at 40 kV and 30 mA powder. X-ray diffraction patterns werecollected over the 20 range 3-50° at a scan rate of 1°/min.

DSC Analysis

DSC was performed on a Mettler Toledo DSC 822e module. 4-6 mg of samplewas placed in crimped but vented aluminium sample pans. The temperaturerange was from 30-250° C. @ 10° C./min. Samples were purged by a streamof nitrogen flowing at 80 mL/min.

IR Analysis

IR was performed on a Fisher Scientific (NICOLET-iS50-FTIR). About 5 mgof sample was spread over the region of diamond ATR sampling station andcollected the sample spectrum between 4000 cm−1 to 400 cm−1 to obtain aspectrum of suitable intensity (above 60% transmission at 2000 cm−1).

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention are further described usingspecific examples herein after. The examples are provided for betterunderstanding of certain embodiments of the invention and not, in anymanner, to limit the scope thereof. Possible modifications andequivalents apparent to those skilled in the art using the teachings ofthe present description and the general art in the field of theinvention shall also form the part of this specification and areintended to be included within the scope of it.

Schemes:

General procedure: To a glass vessel equipped with a stirrer, condenserand a thermometer probe were added the Formula II, Formula III and asuitable first organic solvent and the mass was heated to suitabletemperature. The resulting reaction mass (containing Formula I) wascooled and a co-former selected from Thymine or Adenine was added to thereaction mass. A suitable second organic solvent was added to thereaction mass at constant rate under stirring. The mass was heated to asuitable temperature and the resulting suspension was maintained at thesame temperature under stirring. The mass was cooled and Water was addedto the reaction mass at a constant rate under stirring. The reactionmass was maintained at 25±5° C. The mass was filtered and the solid waswashed, suck dried and dried under vacuum to obtain Dasatinib-co-crystalof Formula B as a crystalline solid.

Example 1a: Preparation of Dasatinib-Thymine Co-Crystal of Formula Iafrom Formula II (Using DMAc and Methanol as the Solvents) One-PotSynthesis

To a 100 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (2.00 g, 0.0051 mol, 1.00equiv.), Formula III (6.00 mL, 3.00 vol) and N,N-dimethyl acetamide(2.00 mL, 1.00 vol) and the mass was heated to 75±2° C. The reactionmass was maintained at 75±2° C. under stirring. The resulting reactionmass (containing Formula I) was cooled to 255° C. and Thymine (0.96 g,0.007 mol, 1.50 equiv.) was added to the reaction mass at 25±5° C. understirring. Methanol (60.0 mL, 30.0 vol) was added to the reaction mass atconstant rate at 25±5° C. under stirring. The mass was heated to 60±2°C. and the resulting suspension was maintained at the same temperatureunder stirring. The mass was cooled to 25±5° C. and maintained at thesame temperature. Water (15 mL, 7.50 vol) was added to the reaction massat a constant rate under stirring. The reaction mass was maintained at25±5° C. The mass was filtered and the solid was washed with Methanol(10.0 mL, 5.00 vol), suck dried and dried at 50±5° C. under vacuum toobtain Dasatinib-Thymine co-crystal of Formula Ia as a crystallinesolid.

Example-1b: Preparation of Dasatinib-Adenine Co-Crystal of Formula Ibfrom Formula II (Using DMAc and Methanol as the Solvents)—One-PotSynthesis

To a 500 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (10.0 g, 0.0254 mol, 1.00equiv.), Formula III (30.0 mL, 3.00 vol) and N, N-dimethyl acetamide(10.0 mL, 1.00 vol) and the mass was heated to 75±5° C. The reactionmass was maintained at 75±5° C. under stirring. The reaction mass wascooled to 25±5° C. and Adenine (5.14 g, 0.038 mol, 1.50 equiv.) wasadded to the reaction mass at 25±5° C. under stirring. Methanol (300 mL,30.0 vol) was added to the reaction mass at constant rate at 25±5° C.under stirring. The mass was heated to 60±2° C. and the resultingsuspension was maintained at the same temperature under stirring. Themass was cooled to 25±5° C. and maintained at the same temperature.Water (130 mL, 13.0 vol) was added to the reaction mass at a constantrate under stirring. The reaction mass was maintained at 25±5° C. Themass was filtered and the solid was washed with Methanol (70.0 mL, 7.00vol), suck dried and dried at 50±5° C. under vacuum to obtainDasatinib-Adenine co-crystal of Formula Ib as a crystalline solid.

Example-1c

To a 3 L glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (50.0 g, 0.127 mol, 1.00equiv.), Formula III (150 mL, 3.00 vol) and N,N-dimethyl acetamide (50.0mL, 1.00 vol) and the mass was heated to 75±5° C. The reaction mass wasmaintained at 75±5° C. under stirring. The reaction mass was cooled to25±5° C. and Adenine (25.7 g, 0.190 mol, 1.50 equiv.) was added to thereaction mass at 25±5° C. under stirring. Methanol (1500 mL, 30.0 vol)was added to the reaction mass at constant rate at 25±5° C. understirring. The mass was heated to 60±2° C. and the resulting suspensionwas maintained at the same temperature under stirring. The mass wascooled to 25±5° C. and maintained at the same temperature. Water (650mL, 13.0 vol) was added to the reaction mass at a constant rate understirring. The reaction mass was maintained at 25±5° C. The mass wasfiltered and the solid was washed with Methanol (350 mL, 7.00 vol), suckdried and dried at 50±5° C. under vacuum to obtain Dasatinib-Adenineco-crystal of Formula Ib as a crystalline solid.

To a glass vessel equipped with a stirrer, condenser and a thermometerprobe were added the Formula II, Formula III and a suitable firstorganic solvent and the mass was heated to a suitable temperature. Thereaction mass was cooled and a suitable second organic solvent was addedat a constant rate under stirring. The mass was filtered. Formula I(wet), was charged into a glass vessel equipped with a stirrer,condenser and a thermometer probe. Co-former selected from Thymine oradenine was added. The mass was heated to a suitable temperature and theresulting suspension was maintained at the same temperature understirring. The mass was cooled and Water was added to the reaction massat a constant rate under stirring. The mass was filtered and the solidwas washed with Methanol, suck dried and dried under vacuum to obtainDasatinib-co-crystal of Formula B as a crystalline solid.

Example 2a: Preparation of Dasatinib-Thymine Co-Crystal of Formula Iafrom Formula II (Using Wet Dasatinib)

To a 100 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (2.00 g, 0.0051 mol, 1.00equiv.), Formula III (6.00 mL, 3.00 vol) and N,N-dimethyl acetamide(2.00 mL, 1.00 vol) and the mass was heated to 752° C. The reaction masswas maintained at 75*2° C. under stirring. The reaction mass was cooledto 25±5° C. and Methanol (50.0 mL, 25.0 vol) was added at a constantrate under stirring. The resulting slurry was stirred at 25±5° C. Themass was filtered and the solid was washed with Methanol (10.0 mL, 5.00vol). Formula I (wet) (2.00 g, 0.0041 mol), was charged into a 100 mLglass vessel equipped with a stirrer, condenser and a thermometer probe.Thymine (0.77 g, 0.006 mol, 1.50 equiv.) and Methanol (60.0 mL, 30.0vol) were added at 25±5° C. The mass was heated to 60±2° C. and theresulting suspension was maintained at the same temperature understirring. The mass was cooled to 25±5° C. and maintained at the sametemperature. Water (15 mL, 7.50 vol) was added to the reaction mass at aconstant rate under stirring. The reaction mass was maintained at 25±5°C. The mass was filtered and the solid was washed with Methanol (10.0mL, 5.00 vol), suck dried and dried at 50±5° C. under vacuum to obtainDasatinib-Thymine co-crystal of Formula Ia as a crystalline solid.

To a glass vessel equipped with a stirrer, condenser and a thermometerprobe were added the Formula II, Formula III, a suitable coformerselected from Thymine or adenine and Methanol. The reaction mass washeated to a suitable temperature. The mass was cooled and filtered andthe solid was washed with Methanol, suck dried and dried under vacuum toobtain Dasatinib-co-crystal of Formula B as a crystalline solid.

Example 3a: Preparation of Dasatinib-Thymine Co-Crystal of Formula Iafrom Formula II (Using Methanol as the Solvent) One-Pot Synthesis

To a 1 L glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (50.0 g, 0.127 mol, 1.00equiv.), Formula III (200 mL, 4.00 vol), Thymine (15.99 g, 0.127 mol,1.00 equiv.) and Methanol (300 mL, 6.00 vol). The reaction mass washeated to 67±2° C. The reaction mass was maintained at 65±2° C. understirring. After completion of the reaction, Methanol (200 mL, 4.00 vol)was added to the reaction mass at constant rate. The reaction mass wasmaintained at the same temperature under stirring. The mass was cooledto 25±5° C. and maintained at the same temperature. The mass wasfiltered and the solid was washed with Methanol (250 mL, 5.00 vol), suckdried and dried at 505° C. under vacuum to obtain Dasatinib-Thymineco-crystal of Formula Ia as a crystalline solid (57.5 g, 91.38% w.r.tFormula II, 99.91% AUC, N-Oxide impurity: <0.15% AUC, N-Deshydroxyethylimpurity: <0.15% AUC).

To a glass vessel equipped with a stirrer, condenser and a thermometerprobe were added the Formula I, and Butanediol and the mass was heatedto 115±5° C. The reaction mass was maintained at 115±5° C. understirring. The reaction mass was cooled to 60±5° C. and maintained at thesame temperature. The mass was filtered and dried under vacuum to obtainDasatinib-Butanediol solvate of Formula Ic or Id or Ie or Ig as acrystalline solid.

Example 4a: Preparation of Crystalline Dasatinib-(±)-1,2-ButanediolSolvate of Formula Ic from Anhydrous Dasatinib

To a 50 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula I (1.00 g, 0.002 mol), and(±)-1,2-Butanediol (10.0 mL, 10.0 vol) and the mass was heated to 115±5°C. The reaction mass was maintained at 115±5° C. under stirring. Thereaction mass was cooled to 60±5° C. and maintained at the sametemperature. The mass was filtered and dried under vacuum to obtainDasatinib-(±)-1,2-Butanediol solvate of Formula Ic as a crystallinesolid.

Example 4b: Preparation of Crystalline Dasatinib-(R)-1, 2-ButanediolSolvate of Formula Id from Anhydrous Dasatinib

To a 50 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula I (1.00 g, 0.002 mol), and(R)-1, 2-Butanediol (10.0 mL, 10.0 vol) and the mass was heated to115±5° C. The reaction mass was maintained at 115±5° C. under stirring.The reaction mass was cooled to 60±5° C. and maintained at the sametemperature. The mass was filtered and dried under vacuum to obtainDasatinib-(R)-1, 2-Butanediol solvate of Formula Id as a crystallinesolid.

Example 4c: Preparation of Crystalline Dasatinib-(±)-2,3-ButanediolSolvate of Formula Ig from Anhydrous Dasatinib

To a 50 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula I (2.00 g, 0.0021 mole, 1.00equiv.), and (±)-2,3-butanediol (15.0 mL, 15.0 vol) and the mass washeated to 115±5° C. The reaction mass was maintained at 115±5° C. understirring for 1 to 2 h (Clear solution). The reaction mass was cooled to60±5° C. and maintained at the same temperature for 3 to 4 h. The masswas filtered and dried under vacuum for 10-15 h to obtain Dasatinib-2,3-butanediol solvate of Formula Ig as a crystalline solid.

To a glass vessel equipped with a stirrer, condenser and a thermometerprobe were added the Formula-II, Formula-III, N,N-Diisopropyl ethylamine and Butanediol was added and the mass was heated to a suitabletemperature. The mass was cooled and filtered. The solid was washed,suck dried under vacuum to obtain Dasatinib-Butanediol solvate ofFormula-Ic or Id or Ie or Ig as a crystalline solid.

Example 5a: Preparation of Crystalline Dasatinib-(S)-1,2-ButanediolSolvate of Formula Ie from Formula II (Using DIPEA and Butanediol as theSolvent)—One-Pot Synthesis

To a 5 L glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula-II (300.0 g, 0.7608 mol.),Formula-III (300 mL, 1.00 vol), N,N-Diisopropyl ethyl amine (688 g, 5.32mol) and (S)-1,2-Butanediol (1500 mL, 5.00 vol) was added and the masswas heated to 115±5° C. The reaction mass was maintained at 115±5° C.under stirring for 13 to 15 h. The mass was cooled to 60±5° C. andmaintained at the same temperature for 1 to 2 h. The mass was filteredand the solid was washed with Diisopropyl ether (1500 mL, 5.00 vol),suck dried under vacuum for 1-2 h and material was dried at 40° C. undervacuum for 12-15 h to obtain Dasatinib-(S)-1,2-Butanediol solvate ofFormula-Ie as a crystalline solid.

To a glass vessel equipped with a stirrer, condenser and a thermometerprobe were added the Formula II, Formula III, N,N-dimethyl acetamide andButanediol and the mass was heated to a suitable temperature. Thereaction mass was cooled and Butanediol was added. The mass was heatedagain to a suitable temperature. The mass was cooled and filtered andthe solid and dried under vacuum obtain Dasatinib-Butanediol solvate ofFormula Ic or Id or Ie or Ig as a crystalline solid.

Example 6a: Preparation of Crystalline Dasatinib-(±)-1,2-ButanediolSolvate of Formula Ic from Formula II (One-Pot Synthesis)

To a 100 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (5.00 g, 0.0127 mol),Formula III (5.00 mL, 1.00 vol), N,N-dimethyl acetamide (2.50 mL, 0.50vol) and (±)-1,2-Butanediol (5.00 mL, 1.00 vol) and the mass was heatedto 115±5° C. The reaction mass was maintained at 115±5° C. understirring. The reaction mass was cooled to 25±5° C. and(±)-1,2-Butanediol (20.0 mL, 4.00 vol) was added. The mass was heated to115±5° C. and the resulting mass was maintained at the same temperatureunder stirring. The mass was cooled to 60±5° C. and maintained at thesame temperature. The mass was filtered and the solid was washed with(±)-1,2-Butanediol (5.00 mL, 1.00 vol), dried under vacuum obtainDasatinib-(±)-1,2-Butanediol solvate of Formula Ic as a crystallinesolid.

To a glass vessel equipped with a stirrer, condenser and a thermometerprobe were added the Formula II, Formula III, N,N-dimethyl acetamide andthe mass was heated to a suitable temperature. (R)-1,2-Butanediol wasadded to the mass and the mass was heated to a suitable temperature. Themass was cooled, filtered and suck dried under vacuum to obtainDasatinib-Butanediol solvate of Formula Ic or Id or Ie or Ig as acrystalline solid.

Example-7a: Preparation of Crystalline Dasatinib-(R)-1,2-ButanediolSolvate of Formula Id from Formula II (One-Pot Synthesis)

To a 50 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (1.00 g, 0.0025 mol) ofFormula III (1.00 mL, 1.00 vol), N,N-dimethyl acetamide (1.20 mL, 1.20vol) and the mass was heated to 90±5° C. The reaction mass wasmaintained at 90±5° C. under stirring for 1 to 2 h. (R)-1,2-Butanediol(10.00 mL, 10.00 vol) was added to the mass and the mass was heated to115±5° C. The reaction mass was maintained at 115±5° C. under stirringfor 1 to 2 h. The mass was cooled to 60±5° C. and maintained at the sametemperature for 2 to 3 h. The mass was filtered and suck dried undervacuum for 12-15 h to obtain Dasatinib-(R)-1,2-Butanediol solvateFormula Id as crystalline solid.

Example-7b: Preparation of Crystalline Dasatinib-(S)-1,2-ButanediolSolvate of Formula Ie from Formula II (One-Pot Synthesis)

To a 500 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula-II (20.0 g, 0.0508 mol.),Formula-III (20.00 mL, 1.00 vol), N,N-dimethyl acetamide (20.00 mL, 1.00vol), mass was heated to 80±5° C. and stirred at 80±5° C. for 3-4 h.(S)-1,2-Butanediol (100 mL, 5.00 vol) was added and the mass was heatedto 115±5° C. The reaction mass was maintained at 115±5° C. understirring for 1 to 2 h. The mass was cooled to 60±5° C. and maintained atthe same temperature for 1 to 2h. The mass was filtered and the solidwas washed with (S)-1,2-Butanediol (20.0 mL, 1.00 vol), suck dried undervacuum for 1-2 h and material was dried at 40° C. under vacuum for 12-15h to obtain Dasatinib-(S)-1,2-Butanediol solvate Formula Ie as acrystalline solid.

Step-1: Preparation of Crystalline Dasatinib-Butanediol Solvate ofFormula Ic or Id or Ie or Ig from Formula II

To a glass vessel equipped with a stirrer, condenser and a thermometerprobe were added the Formula II, Formula III, N, N-Dimethyl acetamideand Triethylamine at 25±5° C. under stirring. The reaction mass washeated to a suitable temperature. After completion of the reaction, thereaction mass was cooled to and Butanediol was added to the reactionmass under stirring. The mass was heated to a suitable temperature. Themass was cooled and filtered, washed the solid with a suitable solventand dried to obtain Dasatinib-Butanediol solvate of Formula Ic or Id orIe or Ig as a crystalline solid.

Step-2: Preparation of Amorphous Dasatinib from CrystallineDasatinib-1,2-Butanediol solvate of Formula I or Id or Ie or Ig

To a 2 L glass vessel equipped with a stirrer, addition funnel and athermometer probe were added of Formula Ic or Id or Ie or Ig, (obtainedby the Example-8, Step-1) Water and Citric acid were added to thereaction mass. The mass was cooled and Aqueous Ammonia was added veryslowly into the reaction mass at a constant rate under stirring. Thereaction mass was warmed, filtered, the solid was washed with water anddried under vacuum to obtain Amorphous Dasatinib.

Example-5a: Preparation of Amorphous Dasatinib from Formula II UsingCrystalline Dasatinib-(±)-1, 2-Butanediol Solvate Formula Ic

Step-1: Preparation of Crystalline Dasatinib-(±)-1, 2-Butanediol Solvateof Formula Ic from Formula II

To a 1 L glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (100 g, 0.253 mol), FormulaIII (100 mL, 1.00 vol), N,N-Dimethyl acetamide (100 mL, 1.00 vol) andTriethylamine (51.33 g, 0.507 mol) was added and the mass was heated to85±2° C. The reaction mass was maintained at 85±2° C. under stirring. Tothe mass was (±)-1, 2-Butanediol (500 mL, 5.00 vol) was added and themass was heated to 120±2° C. The reaction mass was maintained at sametemperature under stirring. The mass was cooled to 65*2° C., filtered,the solid was washed with Toluene (500 mL, 5.0 vol) and dried undervacuum to obtain Dasatinib-(±)-1, 2-Butanediol solvate of Formula Ic asa crystalline solid (120 g).

Step-2: Preparation of Amorphous Dasatinib from CrystallineDasatinib-(±)-1,2-Butanediol Solvate of Formula Ic

To a 1 L glass vessel equipped with a stirrer and a thermometer probewere added the Formula Ic (120 g, obtained by the Example-8b, Step-1),Water (1200 mL, 10.0 vol), Citric acid (73.50 g, 0.507 mol) at 25±5° C.The mass was cooled to 10±5° C. under stirring. Aqueous Ammonia wasadded very slowly into the reaction mass at a constant rate understirring. The reaction mass was warmed to 25±5° C., the solid materialwas filtered, washed with water (1000 mL, 10.0 vol) and dried at 55±5°C. under vacuum to obtain to obtain Amorphous Dasatinib as a solid (94.5g, 76.35% w.r.t. Formula II, 99.8% AUC, N-Oxide impurity: <0.15% AUC,N-Deshydroxyethyl impurity: <0.15% AUC).

Example 9: Preparation of Anhydrous Dasatinib from Formula II

To a 2 L glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (50.0 g, 0.127 mol), FormulaIII (200 mL, 4.00 vol) and Methanol (300 mL, 6.00 vol) was added and themass was heated to 67±2° C. The reaction mass was maintained at 67±2° C.under stirring. Methanol (200 mL, 4.00 vol) and water (100 mL, 2.00 vol)were added. The mass was cooled to 25±5° C. and maintained at the sametemperature. The mass was filtered and the solid was washed withmethanol (250 mL, 5.00 vol) and dried at 55±5° C. under vacuum to obtainAnhydrous Dasatinib as a crystalline solid (45.0 g, 72.71% w.r.t.Formula II, 99.85% AUC, N-Oxide impurity: <0.15% AUC, N-Deshydroxyethylimpurity: <0.15% AUC)

Example 10: Preparation of Amorphous Dasatinib from Formula II UsingAnhydrous Dasatinib

To a 5 L glass vessel equipped with a stirrer and a thermometer probewere added the anhydrous Dasatinib (250 g, 0.512 mol, 1.00 equiv.obtained by using the representative procedure of Example-9), Water(2500 mL, 10.0 vol), Citric acid (590 g, 3.073 mol, 6.00 equiv.) at25±5° C. The mass neutralised with Aq. Ammonia solution (625 ml, 2.5vol) at 25±5° C. The solid material was filtered, washed with water(1250 mL, 5.0 vol), suck dried, and dried at 505° C. under vacuum toobtain Amorphous Dasatinib of Formula I as a solid (235 g).

Example-11: Preparation of Dasatinib Monohydrate from Formula II UsingAnhydrous Dasatinib

Step-1: Preparation of Anhydrous Dasatinib from Formula II

To a 3 L glass vessel equipped with a stirrer, condenser and athermometer probe were added the Formula II (150 g, 0.380 mol), FormulaIII (600 mL, 4.00 vol) and Methanol (900 mL, 6.00 vol) and the mass washeated to 67±2° C. The reaction mass was maintained at 67±2° C. understirring. Methanol (300 mL, 2.00 vol) and water (300 mL, 2.00 vol) wereadded into the reaction mass. The reaction mass was cooled to 25±5° C.and maintained at the same temperature. The mass was filtered, the solidwas washed with Methanol (750 mL, 5.00 vol) and dried at 55±5° C. undervacuum to obtain Anhydrous Dasatinib as a crystalline solid (142 g,76.5% wrt Formula II).

Step-2: Preparation of Dasatinib Monohydrate from Anhydrous Dasatinib

To a 500 mL glass vessel equipped with a stirrer, condenser and athermometer probe were added Anhydrous Dasatinib (40.0 g, obtained bythe Example-18, Step-1) and water (400 mL, 10.0 vol). The mass washeated between 85 and 90° C. and maintained at the same temperatureunder stirring. The mass was cooled to 25±5° C. and maintained at thesame temperature. The mass was filtered, the solid was washed with water(200 mL, 5.00 vol) and dried at 55±5° C. under vacuum to obtainDasatinib Monohydrate as a crystalline solid (38.0 g, 91.62%, 99.92%AUC, N-Oxide impurity: <0.15% AUC, N-Deshydroxyethyl impurity: <0.15%AUC).

The invention claimed is:
 1. A dasatinib butanediol solvate.
 2. Acrystalline dasatinib butanediol solvate, of Formula Ic or Id or Ie orIg

wherein Butanediol is selected from (±)-1, 2-Butanediol (Ic) or (R)-1,2-Butanediol (Id) or (S)-1, 2-Butanediol (Ie) or (±)-2, 3-Butanediol(Ig).
 3. The crystalline dasatinib (±)-1,2-Butanediol solvate of FormulaIc of claim 2

which is characterised by an XPRD pattern comprising peaks atapproximately 5.61±0.2, 10.99±0.2, 11.22±0.2, and 24.11±0.2 degrees 2θ.4. The crystalline dasatinib (±)-1,2-Butanediol solvate of Formula Ic ofclaim 2

which is characterised by a differential scanning calorimetry thermogramhaving peaks approximately at 169 and 285° C.
 5. The crystallinedasatinib (R)-1,2-Butanediol solvate of Formula Id of claim 2

which is characterised by an XPRD pattern comprising peaks atapproximately 5.69±0.2, 11.30±0.2, 12.62±0.2, and 17.35±0.2 degrees 2θ.6. The crystalline dasatinib (S)-1,2-Butanediol solvate of Formula Ie ofclaim 2

which is characterised by an XPRD pattern comprising peaks atapproximately 5.56±0.2, 11.18±0.2, 16.81±0.2, and 17.12±0.2 degrees 2θ.7. The crystalline dasatinib (±)-2, 3-Butanediol solvate of Formula Igof claim 2

which is characterised by an XPRD pattern comprising peaks atapproximately 5.67±0.2, 11.35±0.2, 17.06±0.2, and 17.29±0.2 degrees 2θ.8. A process for the preparation of crystalline Dasatinib-Butanediolsolvate of Formula Ic or Id or Ie or Ig, comprising the following steps,treating the dichloro intermediate of Formula II

with 2-(piperazin-1-yl) ethan-1-ol of Formula III

in the presence of suitable organic solvent and a suitable organic baseat a suitable temperature to obtain Formula I (In-situ)

treating the mass containing the Formula I with a suitable Butanediol,to obtain crystalline Dasatinib-Butanediol solvate of Formula Ic or Idor Ie or Ig,

wherein Formula Ic=Dasatinib-(±)-1, 2-Butane diol solvate, FormulaId=Dasatinib-(R)-1, 2-Butanediol solvate, Formula Ie=Dasatinib-(S)-1,2-Butanediol solvate, and Formula Ig=Dasatinib-(±)-2, 3-Butane diolsolvate.
 9. The process of claim 8, wherein the suitable organic base isselected from the group consisting of tertiary amines.
 10. The processof claim 9, wherein the tertiary amine is N,N-diisopropylethylamine ortriethylamine.
 11. The process of claim 8, wherein the suitable organicsolvent is selected from dimethyl sulfoxide and N,N-dimethyl acetamide.12. A process for the preparation of amorphous Dasatinib, comprising thefollowing steps, treating the dichloro intermediate of Formula II

with 2-(piperazin-1-yl) ethan-1-ol of Formula III

in the presence of a suitable organic solvent and a suitable organicbase to obtain Dasatinib of Formula I (in-situ)

followed by treating the reaction mass with a suitable Butanediol toobtain a crystalline Dasatinib-Butanediol solvate of Formula Ic or Id orIe or Ig,

and treating the crystalline Dasatinib-Butanediol solvate of Formula Icor Id or Ie or Ig with a citric acid solution followed by treating withan aqueous ammonia solution to obtain amorphous Dasatinib.
 13. Theprocess for the preparation of amorphous Dasatinib of claim 12, whereinthe suitable organic solvent is selected from the group consisting ofsulfoxide and amide solvents.
 14. The process for the preparation ofamorphous Dasatinib of claim 12, wherein the suitable organic base isselected from the group consisting of tertiary amines.